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.
The New England journal of medicine
November 3, 2022
Guy M. Goodwin, Scott T Aaronson, Oscar Alvarez et al.
1,095 citations
A single 25 mg dose of psilocybin, but not 10 mg, reduced depression scores more than a 1 mg control dose over three weeks in adults with treatment-resistant depression. In this phase 2 trial, 233 participants were randomly assigned to 25 mg, 10 mg, or 1 mg of synthetic psilocybin with psychological support. The 25 mg group showed an average 12-point drop on the MADRS depression scale versus a 5.4-point drop in the 1 mg group, a significant difference. The 10 mg group did not differ significantly from control. Response and remission rates at three weeks supported the primary result, but sustained response at 12 weeks was not significantly different.
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.
Neuropsychopharmacology
April 26, 2017
Robin Carhart-Harris, Guy M. Goodwin
680 citations
Plant-based psychedelics like psilocybin have ancient medicinal roots. After LSD's first English-language report in 1950, psychedelics briefly aided psychotherapy for mood disorders and alcohol dependence before prohibitive legislation in the mid-1960s halted major research. Since the early 1990s, human psychedelic research has revived, with recent reports including the first modern brain imaging study with LSD and three clinical trials of psilocybin for depressive symptoms. The authors offer opinions on the promises and pitfalls of renewed research, focusing on developing psilocybin as a depression treatment.
J Psychopharmacol
February 15, 2018
Robin Carhart-Harris, Leor Roseman, Eline Haijen et al.
646 citations
Modern trials support the therapeutic potential of psychedelic drugs, but their effects are exceptionally sensitive to context—the combination of mindset and physical setting. This opinion piece highlights how classic psychedelics act through 5-HT2A receptor agonism and associated plasticity, making context crucial. It proposes a study design to test positive interactions between psychedelics and context, and presents new findings on how contextual determinants shape the quality of a psychedelic experience, which in turn predicts long-term mental health outcomes. The authors aim to inform good practice, optimize treatment models, and reduce stigma while building evidence that context minimizes harms and maximizes benefits.
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.
Curr Biol
April 13, 2016
Enzo Tagliazucchi, Leor Roseman, Mendel Kaelen et al.
531 citations
LSD, a potent serotonin-receptor agonist, increases global functional connectivity in the human brain, particularly in high-level association cortices and the thalamus, as shown by fMRI. These effects overlap with serotonin 2A receptor densities and correlate with subjective reports of ego dissolution. The drug also enhances communication between normally distinct brain networks, reducing the brain's modular and rich-club organization. This is the first modern human imaging study of LSD's acute effects on brain connectivity, demonstrating that LSD selectively expands global connectivity and blurs perceptual boundaries between self and environment.
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.
Scientific Reports
April 19, 2017
Michael Schartner, Robin Carhart-Harris, Adam B. Barrett et al.
450 citations
Measures of neural signal diversity, such as entropy and Lempel-Ziv complexity, are higher during wakeful rest than during anesthesia. In this study, these measures were computed for spontaneous magnetoencephalographic signals from humans under psilocybin, ketamine, and LSD. All three psychedelics produced reliably higher signal diversity, even after controlling for spectral changes, with the most pronounced increase in temporal (single-channel LZ complexity) rather than spatial diversity. Selective correlations emerged between changes in signal diversity and the intensity of psychedelic experience. This is the first time these measures have been applied to the psychedelic state and have yielded values exceeding normal waking consciousness, suggesting that psychedelic phenomenology constitutes an elevated level of consciousness.
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.
J Psychopharmacol
July 11, 2019
Leor Roseman, Eline Haijen, Kelvin Idialu-Ikato et al.
415 citations
Emotional breakthrough—a sudden release or shift in emotion during a psychedelic experience—is a distinct and important component that predicts long-term psychological changes, separate from mystical-type experiences. A six-item Emotional Breakthrough Inventory was validated in 379 participants who completed surveys before and after a planned psychedelic experience. Emotional breakthrough scores were dose-dependent and higher when the psychedelic was taken with therapeutic intent. In a subsample of 75 participants with low baseline well-being, emotional breakthrough, mystical experience, and challenging experience scores together significantly predicted changes in well-being (r=0.45). Emotional breakthrough and mystical experience scores predicted increases in well-being, while challenging experience scores predicted smaller increases.
Frontiers in Psychology
September 4, 2018
Raphaël Millière, Robin Carhart-Harris, Leor Roseman et al.
402 citations
Both meditation and psychedelic drugs like psilocybin and LSD can disrupt the sense of self, but these disruptions are not uniform. Meditation traditions aim to dissolve the self through altered states, while psychedelics produce drug-induced ego dissolution via serotonin receptor agonism. The authors argue that self-consciousness is a multidimensional construct, with narrative aspects (autobiographical memory, self-related thoughts) and embodied aspects (multisensory processes) being differently affected by each. They caution against conflating temporary self-loss with long-term selflessness as a trait, though preliminary evidence suggests possible correlations. The article calls for nuanced understanding of these phenomena.
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.
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.
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.