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.
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.
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.
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 D. G. 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.
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.
The International Journal of Neuropsychopharmacology
October 21, 2022
James J Gattuso, Daniel Perkins, Simon Ruffell et al.
233 citations
Classical psychedelics like LSD, psilocybin, and ayahuasca consistently disrupt resting-state connectivity within the Default Mode Network (DMN) and increase functional connectivity between canonical resting-state networks. The DMN, a set of brain regions active during self-referencing and mind wandering, is altered in various neuropsychiatric conditions. While DMN modulation is central to some cognitive models of psychedelics, its role in their therapeutic potential remains unclear. This systematic review provides a comprehensive overview to guide future research on the neurocognitive mechanisms of these agents.
Frontiers in Pharmacology
March 31, 2022
Roberta Murphy, Roberta Murphy, Hannes Kettner et al.
229 citations
In a trial comparing psilocybin-assisted therapy to escitalopram for moderate-to-severe depression, a stronger therapeutic alliance with the therapist predicted greater emotional breakthrough and mystical-type experiences during psilocybin sessions, and these experiences in turn predicted larger reductions in depression symptoms six weeks after treatment. Emotional breakthrough during the first session strengthened the alliance before the second session, while a weaker alliance before the second session directly predicted higher depression scores at the endpoint, independent of the acute psychedelic experience. The findings suggest the therapeutic relationship plays a key role in shaping both the quality of the psychedelic experience and clinical outcomes.
Frontiers in Psychology
August 15, 2018
Christopher Timmermann, Leor Roseman, L. Williams et al.
228 citations
Near-death experiences (NDEs) share striking phenomenological similarities with the effects of the psychedelic drug DMT. In a placebo-controlled, within-subjects study, 13 healthy participants received DMT and placebo, then completed a standard NDE measure. DMT significantly increased NDE-like features compared to placebo. NDE scores were linked to DMT-induced ego-dissolution and mystical experiences, as well as baseline traits of absorption and delusional ideation. Nearly all NDE features overlapped between DMT-induced experiences and a matched group of actual NDE experiencers. These results indicate a remarkable similarity between the DMT state and NDEs, warranting further research.
Journal of Psychopharmacology
January 16, 2020
Lea J. Mertens, Matthew B. Wall, Leor Roseman et al.
211 citations
After a single 25 mg dose of psilocybin, patients with treatment-resistant depression showed decreased functional connectivity between the ventromedial prefrontal cortex and the right amygdala while viewing faces, particularly fearful and neutral ones. This decrease was linked to lower rumination levels one week later. Increased connectivity between these regions and occipital-parietal cortices also emerged. The findings suggest psilocybin therapy may revive emotional responsiveness at both neural and psychological levels, offering a potential treatment mechanism. Placebo-controlled studies are needed to confirm these results.
Biological Psychiatry
January 10, 2014
Robin Carhart‐Harris, Kevin Murphy, Robert Leech et al.
182 citations
The medial temporal lobes (MTLs) are specifically involved in how MDMA works in the brain, though more research is needed to understand how the drug's characteristic subjective effects emerge from its modulation of spontaneous brain activity.
BJPsych Open
December 23, 2021
Zach Walsh, Özden Merve Mollaahmetoğlu, Joseph M. Rootman et al.
180 citations
A systematic review of 83 studies found that subanesthetic doses of ketamine produce rapid, short-lived antidepressant and anti-suicidal effects. Evidence for other psychiatric conditions is less robust but suggests similarly positive but transient benefits. The conclusions are tentative due to high risk of bias across the included studies. Optimal dosing, administration methods, and best forms of adjunctive psychotherapy require further investigation.
Psychopharmacology
August 8, 2022
Rosalind Watts, Hannes Kettner, Dana Geerts et al.
159 citations
A new scale, the Watts Connectedness Scale (WCS), measures a three-dimensional sense of connectedness to self, others, and the wider world. Analysis of data from 1,226 participants in online surveys and a randomized controlled trial of 52 people with major depressive disorder showed the scale has good internal consistency and construct validity. After psychedelic use, total connectedness scores increased significantly, and acute experiences of mystical experience, emotional breakthrough, and communitas correlated with these changes. In the trial, psilocybin-assisted therapy produced greater increases in WCS scores than daily escitalopram. The WCS may sensitively capture therapeutically relevant psychological changes.
Frontiers in Psychiatry
March 20, 2019
Ben Sessa, David Nutt, Laurie Higbed
141 citations
This review describes the history, pharmacology, safety, and clinical uses of MDMA. Most clinical research has focused on MDMA-assisted psychotherapy for PTSD, which is now in Phase 3 trials with a target for FDA and EMA licensing in 2021. The paper also covers other potential applications, including treating anxiety in autism and the authors' ongoing study on MDMA-assisted psychotherapy for alcohol use disorder. If efficacy criteria are met, MDMA would become a licensed medicine.
Dialogues in Clinical Neuroscience
June 30, 2019
David Nutt
131 citations
Classical psychedelic drugs like psilocybin and LSD, plus MDMA (ecstasy), were used extensively in psychiatric research before being prohibited. The ban stopped research and clinical treatments that had shown promise, though recreational use continued. In the past decade, groups have re-evaluated these substances in medicine. Preliminary data show promise for psilocybin in anxiety, depression, smoking, and alcoholism, and for MDMA in post-traumatic stress disorder and alcoholism. The European Medicines Agency approved psilocybin for a phase 3 study in treatment-resistant depression, and the FDA approved MDMA for PTSD. Results are expected in 2020; positive outcomes could lead to clinical approval soon after.