Lancet Psychiatry
May 17, 2016
Robin Carhart-Harris, Mark Bolstridge, James Rucker et al.
1,546 citations
In an open-label trial, 12 patients with moderate-to-severe treatment-resistant depression received two doses of psilocybin (10 mg and 25 mg, one week apart) in a supportive setting. The psychedelic effects peaked 2-3 hours after dosing and subsided within 6 hours. No serious adverse events occurred; transient anxiety, confusion, nausea, and headache were noted. Depressive symptoms, measured with the Quick Inventory of Depressive Symptoms, were markedly reduced one week after the high dose (mean reduction of 11.8 points) and remained lower at three months (mean reduction of 9.2 points). Improvements in anxiety and anhedonia were also observed. The results provide preliminary support for psilocybin's safety and efficacy in treatment-resistant depression, warranting further controlled trials.
New England Journal of Medicine
April 14, 2021
Robin Carhart-Harris, Bruna Giribaldi, Rosalind Watts et al.
1,372 citations
In a selected group of patients, psilocybin did not show a significantly greater antidepressant effect than escitalopram based on depression scores at week 6. Secondary outcomes generally favored psilocybin, but these analyses were not corrected for multiple comparisons. The authors call for larger and longer trials to compare psilocybin with established antidepressants.
Frontiers in Human Neuroscience
January 1, 2014
Robin Carhart-Harris, Robert Leech, Peter J. Hellyer et al.
1,289 citations
Entropy, a measure of uncertainty or disorder, is applied to brain function and consciousness, focusing on the psychedelic state induced by psilocybin. The psychedelic state is considered a primary or primitive state of consciousness, characterized by elevated entropy in brain function, including a greater repertoire of functional connectivity motifs that form and fragment over time. This suggests primary states may exhibit criticality, a transition zone between order and disorder. Normal waking consciousness suppresses entropy, operating just below criticality, which constrains cognition and enables metacognitive functions like reality-testing and self-awareness. Entry into primary states involves collapse of default-mode network activity and decoupling from medial temporal lobes. These hypotheses can be tested by comparing brain activity in REM sleep, early psychosis, normal waking consciousness, and anesthesia.
Proceedings of the National Academy of Sciences
January 23, 2012
Alessandro Colasanti, Robin J. Tyacke, Robert Leech et al.
1,191 citations
Psychedelic drugs like psilocybin, found in magic mushrooms, produce profound changes in consciousness by decreasing activity and connectivity in key brain hub regions. Using functional MRI, researchers observed that psilocybin reduced cerebral blood flow and BOLD signal, especially in the thalamus, anterior cingulate cortex (ACC), and posterior cingulate cortex (PCC). Decreased activity in the ACC and medial prefrontal cortex (mPFC) predicted the intensity of subjective psychedelic effects. Psilocybin also reduced positive coupling between the mPFC and PCC. These findings suggest that psychedelics work by dampening the brain's connector hubs, leading to a state of unconstrained cognition.
Proc Natl Acad Sci U S A
April 11, 2016
Robin Carhart-Harris, Suresh Muthukumaraswamy, Leor Roseman et al.
887 citations
LSD produces marked changes in brain activity that correlate with its psychological effects. Increased blood flow in the visual cortex, decreased alpha power there, and an expanded functional connectivity profile of the primary visual cortex strongly correlated with visual hallucinations, suggesting that intrinsic brain activity influences visual processing more during the psychedelic state. Decreased connectivity between the parahippocampus and retrosplenial cortex correlated strongly with ego-dissolution and altered meaning, indicating this circuit's role in maintaining the self and processing meaning. Different imaging metrics showed strong relationships, allowing firmer inferences about their functional significance.
Frontiers in Pharmacology
January 17, 2018
Leor Roseman, David Nutt, Robin Carhart-Harris
814 citations
In patients with treatment-resistant depression given psilocybin, the quality of the acute psychedelic experience—specifically the intensity of oceanic boundlessness (a mystical-type experience) and dread of ego dissolution (anxiety-like experience)—predicted improvements in depressive symptoms at 5 weeks. Sensory perceptual effects had negligible predictive value. The findings support the view that the subjective quality of the psychedelic experience is a key mediator of long-term mental health changes, suggesting that therapeutic approaches should aim to enhance mystical-type experiences and reduce anxiety.
Journal of The Royal Society Interface
October 29, 2014
Giovanni Petri, Paul Expert, Federico Turkheimer et al.
689 citations
Functional brain networks can be studied through homological cycles—topological objects that capture mesoscopic structure in weighted correlation networks. A new method, homological scaffolds, compactly represents these cycles and makes them amenable to standard network analysis. Applied to resting-state fMRI data from 15 healthy volunteers given placebo or psilocybin, the homological structure of brain activity changed dramatically after psilocybin, producing many transient, low-stability cycles and a few persistent ones absent under placebo.
Sci Rep
October 13, 2017
Robin Carhart-Harris, Leor Roseman, Mark Bolstridge et al.
590 citations
In patients with treatment-resistant depression, a single dose of psilocybin combined with psychological support reduced depressive symptoms and altered brain activity and connectivity. Functional MRI scans before and after treatment showed decreased blood flow in the temporal cortex, including the amygdala, and increased resting-state functional connectivity within the default-mode network. Reduced amygdala blood flow correlated with fewer depressive symptoms. Changes in connectivity between the ventromedial prefrontal cortex and inferior lateral parietal cortex, as well as between the parahippocampus and prefrontal cortex, predicted treatment response at five weeks. These brain changes differ from the drug's acute effects and suggest a 'reset' of neural circuits.
Journal of Humanistic Psychology
June 19, 2017
Rosalind Watts, Camilla Day, Jacob Krzanowski et al.
582 citations
In an open-label trial, 20 patients with treatment-resistant depression described their experiences six months after psilocybin treatment. They reported two main shifts: from feeling disconnected from themselves, others, and the world to feeling connected, and from avoiding emotions to accepting them. Patients contrasted psilocybin with conventional treatments like medications and short-term talking therapies, which they said reinforced disconnection and avoidance, whereas psilocybin encouraged connection and acceptance. The findings suggest psilocybin may work through a novel mechanism opposite to standard antidepressants and some therapies.
Journal of Neuroscience
September 18, 2013
Matthew J. Brookes, David Errtizoe, Ben Sessa et al.
501 citations
Psychedelic drugs like psilocybin produce profound changes in consciousness by desynchronizing ongoing oscillatory rhythms in the cortex. Using magnetoencephalography in healthy participants, psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices and from 8 to 100 Hz in frontal association cortices, with large decreases in default-mode network areas. Low-level visually induced and motor-induced gamma-band oscillations were unaffected, suggesting some basic oscillatory activity is preserved. Dynamic causal modeling indicated that posterior cingulate cortex desynchronization results from increased excitability of deep-layer pyramidal neurons rich in 5-HT 2A receptors.
Frontiers in Human Neuroscience
June 14, 2016
Matthew M. Nour, Lisa Evans, David Nutt et al.
476 citations
A new questionnaire, the Ego-Dissolution Inventory (EDI), reliably measures the experience of ego-dissolution—a temporary loss of the sense of self—during psychedelic drug use. The EDI shows strong psychometric properties, including internal consistency and construct validity, and its scores closely relate to the subjective psychedelic experience. This tool enables researchers to investigate the brain mechanisms underlying ego-dissolution, which may inform psychedelic-assisted psychotherapy and improve understanding of psychosis.
Nat Med
April 11, 2022
Richard E. Daws, Christopher Timmermann, Bruna Giribaldi et al.
432 citations
Psilocybin therapy produces rapid and sustained antidepressant effects that correlate with a global increase in brain network integration. In two clinical trials, one open-label in treatment-resistant depression and one double-blind randomized controlled trial comparing psilocybin with escitalopram in major depressive disorder, functional MRI showed that psilocybin reduced brain network modularity, making higher-order functional networks more interconnected and flexible. The antidepressant response to escitalopram was milder, with no changes in brain network organization. These consistent efficacy-related brain changes across both studies suggest that psilocybin's antidepressant mechanism involves global increases in brain network integration.
Human Brain Mapping
July 3, 2014
Enzo Tagliazucchi, Robin Carhart-Harris, Robert Leech et al.
423 citations
Psilocybin, the active compound in magic mushrooms, increases the variability and range of brain activity and connectivity. Using fMRI, fifteen healthy volunteers were scanned before, during, and after receiving psilocybin or a placebo. Psilocybin raised the variability of blood-oxygen-level-dependent signals in the hippocampi and anterior cingulate cortex. Changes in the spectral behavior of brain signals were limited to higher-order networks, including the default mode, executive control, and dorsal attention networks. The brain also explored a wider repertoire of connectivity states after psilocybin than under control conditions. These findings help explain the unconstrained, hyper-associative quality of consciousness in the psychedelic state.
Frontiers in Pharmacology
November 2, 2018
Adam Hampshire, Christopher Timmermann, Christopher Timmermann et al.
422 citations
Psychological well-being increased two weeks after a psychedelic experience and remained elevated at four weeks. Higher ratings of a 'mystical-type experience' positively influenced this change in well-being, while 'challenging experience' and 'visual effects' did not. Having 'clear intentions' for the experience fostered mystical-type experiences. A positive 'set' and recreational intentions reduced the likelihood of a challenging experience. The trait 'absorption' and higher drug doses amplified all aspects of the acute experience. Baseline traits had the strongest effect on well-being change, underscoring the importance of extra-pharmacological factors in shaping responses to psychedelics.
Acta Psychiatrica Scandinavica
October 30, 2020
Kristoffer Andreas Aamodt Andersen, Robin Carhart-Harris, David Nutt et al.
352 citations
A systematic review of 16 papers from 10 clinical trials (7 with psilocybin, 2 with ayahuasca, 1 with LSD) found that serotonergic psychedelics show promise for treating depression, anxiety, obsessive-compulsive disorder, and substance use disorders. Across 188 patients with cancer- or illness-related anxiety and depression, major depressive disorder, OCD, or substance use disorder, the therapy appeared safe, with no severe adverse events reported. Therapeutic effects often lasted weeks to months after only 1 to 3 treatment sessions. The evidence supports feasibility and early efficacy, though larger trials are needed.
Human Brain Mapping
May 22, 2015
Alexander V. Lebedev, Martin Lövdén, Gidon Rosenthal et al.
347 citations
Psilocybin, the active compound in magic mushrooms, produces ego-dissolution—a feeling that the self is disintegrating or that the boundary between self and world is dissolving—similar to ego-disturbances seen in schizophrenia. In a placebo-controlled study of 15 healthy volunteers, functional MRI scans showed that psilocybin-induced ego-dissolution was linked to decreased connectivity between the medial temporal lobe and high-level cortical regions, disintegration of the salience network, and reduced communication between brain hemispheres. Individuals with lower diversity of executive network nodes at baseline were more likely to experience ego-dissolution. These findings suggest that maintaining a coherent sense of self depends on normal functioning of these brain systems.
Neuropharmacology
December 25, 2017
James J.H. Rucker, Jonathan Iliff, David Nutt
339 citations
Classical psychedelics like psilocybin, LSD, and mescaline were widely used in psychiatry before being placed in Schedule I of the UN Convention on Drugs in 1967. Pre-prohibition studies indicate these drugs are not helpful for people with established psychotic disorders and should be avoided in those at risk. However, individuals with psychoneurotic disorders sometimes benefited considerably from the drugs' tendency to loosen fixed, maladaptive patterns of cognition and behavior, especially in a supportive therapeutic setting. A recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. Serious adverse events appear to be low. Since 2006, pilot trials and randomized controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders have provided encouraging results, though regulatory and legal hurdles to licensing remain formidable.
Cell
April 1, 2020
David Nutt, David Erritzøe, Robin Carhart-Harris
330 citations
Following a decades-long global halt in psychedelic research, new investigations into drugs like psilocybin that act on the 5-HT2A receptor are showing promise for treating serious psychiatric disorders, including depression and addiction. Neuroscience and clinical studies are yielding exciting results in this area.
Sci Rep
November 19, 2019
Christopher Timmermann, Leor Roseman, Michael Schartner et al.
325 citations
Intravenous DMT, a fast-acting psychedelic, markedly reduces alpha and beta brain wave power and increases spontaneous signal diversity in the human brain, as measured by EEG. The emergence of delta and theta oscillatory activity correlates with the peak of the subjective experience, especially its eyes-closed visual component. Relationships between changes in subjective experience and brain activity were observed across time, linking specific brain changes to specific aspects of the experience.
J Psychopharmacol
February 2, 2022
Anne K. Schlag, Jacob S. Aday, Iram Salam et al.
319 citations
Classic psychedelics carry minimal medical risks such as toxicity and overdose, and many persistent negative perceptions of psychological risks—including abuse liability and dependence—are unsupported by current scientific evidence when use occurs in regulated or medical contexts. Most reported adverse effects are not observed under these conditions. The review underscores the need for clinicians and therapists to maintain high safety and ethical standards and for balanced media reporting to avoid future controversies and allow continued research.
Psychological Medicine
February 5, 2016
Robin Carhart-Harris, Mendel Kaelen, Mark Bolstridge et al.
301 citations
A single intravenous dose of LSD (75 µg) in 20 healthy volunteers produced robust acute psychological effects, including heightened mood and elevated scores on a measure of psychosis-like symptoms. Two weeks later, participants showed increased optimism and trait openness compared to after placebo, with no changes in delusional thinking. The findings suggest that psychedelics can acutely induce psychosis-like symptoms yet improve psychological wellbeing in the mid to long term. The authors propose that acute mood changes stem from a more fundamental modulation of cognition, and that increased cognitive flexibility from serotonin 2A receptor stimulation promotes emotional lability during intoxication and leaves a lasting loosened cognition conducive to improved wellbeing.
Frontiers in Human Neuroscience
May 27, 2014
Leor Roseman, Robert Leech, Amanda Feilding et al.
293 citations
Psychedelic drugs like psilocybin and MDMA perturb consciousness in distinct ways, offering a tool to study brain mechanisms underlying conscious states. In placebo-controlled studies, psilocybin increased resting-state functional connectivity between brain networks, making them less differentiated, while decreasing connectivity between visual and sensorimotor networks. MDMA produced less marked changes in between-network connectivity, suggesting that the extensive network alterations under psilocybin may be unique to classic psychedelics and relate to their profound effects on consciousness. This analytical approach could help characterize other altered conscious states.
Psychopharmacology
February 1, 2018
Mendel Kaelen, Bruna Giribaldi, Jordan Raine et al.
274 citations
Music plays a central therapeutic role in psychedelic therapy with psilocybin for treatment-resistant depression. In interviews with 19 patients, music had both welcome influences—evoking meaningful emotion, mental imagery, guidance, openness, calm, and safety—and unwelcome influences, such as unpleasant emotion, imagery, and resistance. Patients' experience of the music correlated with mystical experiences and insightfulness. Critically, the nature of the music experience significantly predicted reductions in depression one week after psilocybin, whereas general drug intensity did not.
Schizophrenia Bulletin
October 6, 2012
Robin Carhart-Harris, Robert Leech, David Erritzøe et al.
267 citations
Psilocybin, a classic psychedelic, increases functional connectivity between the default-mode network (DMN) and task-positive network (TPN), reducing the normal orthogonality between these networks. In 15 healthy volunteers, intravenous psilocybin (vs placebo) during resting-state fMRI scans led to greater DMN-TPN connectivity, a pattern also seen in psychosis and meditative states. Thalamocortical connectivity remained unchanged, suggesting it relates to arousal rather than the separateness of internal versus external focus. The findings support psilocybin as a model for early psychosis, where compromised DMN-TPN orthogonality may explain phenomenological overlaps.
Neuroimage
May 25, 2019
Louis-David Lord, Paul Expert, Selen Atasoy et al.
249 citations
Brain function can be understood as the exploration of a repertoire of metastable connectivity patterns that underlie different mental processes. Intravenous infusion of psilocybin rapidly modulates how the brain dynamically explores these resting-state networks. Using a data-driven approach focused on the leading eigenvector of BOLD phase coherence at single-TR resolution, recurrent BOLD phase-locking patterns were assessed pre- and post-infusion. A frontoparietal subsystem pattern was strongly destabilized after psilocybin, while a pattern characterized by global BOLD phase coherence became more probable. These results demonstrate network-specific neuromodulation by psilocybin, bridging molecular pharmacodynamics and whole-brain network dynamics.