Lancet Psychiatry
May 17, 2016
Robin L 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.
Proc Natl Acad Sci U S A
April 11, 2016
Robin L. 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.
J Psychopharmacol
February 15, 2018
Robin L 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 L 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.
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.
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.
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.
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.
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.
Acta Psychiatrica Scandinavica
June 19, 2018
David Erritzøe, Leor Roseman, Matthew M. Nour et al.
268 citations
In patients with treatment-resistant depression, psilocybin therapy was associated with a decrease in neuroticism and increases in extraversion and openness three months later. These personality shifts moved toward normative population averages and were predicted by the degree of insight experienced during the psilocybin session. Conscientiousness showed trend-level increases, while agreeableness did not change. The pattern partly resembles changes seen with conventional antidepressants, but the pronounced rises in extraversion and openness may be more specific to psychedelic therapy.
Psychopharmacology
August 9, 2017
Robin Carhart‐Harris, David Erritzøe, Eline Haijen et al.
268 citations
Psychedelic drugs show therapeutic potential in psychiatry, but how they work is unclear. The authors propose that a sense of connectedness is key to their effectiveness, provide preliminary evidence supporting this idea, and outline a roadmap for further testing.
Sci Rep
December 15, 2017
Selen Atasoy, Leor Roseman, Mendel Kaelen et al.
225 citations
LSD alters the energy and power of individual harmonic brain states in a frequency-selective manner, leading to an expansion of the repertoire of active brain states. This expansion is non-random, suggesting a general re-organization of brain dynamics. The frequency distribution of active brain states under LSD closely follows power-laws, indicating a re-organization of dynamics at the edge of criticality. These findings provide insight into how LSD affects brain function and open new methods for understanding complex brain dynamics in health and disease.
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.
Eur Neuropsychopharmacol
April 12, 2016
Mendel Kaelen, Leor Roseman, Joshua Kahan et al.
143 citations
Psychedelic drugs like LSD are being re-examined for therapeutic use, often combined with music during psychotherapy. In a placebo-controlled fMRI study with 12 healthy volunteers, researchers investigated how LSD and music together affect mental imagery. They found that the combination of LSD and music increased functional connectivity and information flow from the parahippocampal cortex to the visual cortex. This enhanced connectivity correlated with stronger eyes-closed visual imagery, including autobiographical imagery. The findings suggest a neural mechanism by which music and LSD synergistically enhance subjective experiences that may be valuable in therapeutic settings.
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.
The International Journal of Neuropsychopharmacology
December 17, 2013
Robin Carhart‐Harris, Matthew B. Wall, David Erritzøe et al.
110 citations
MDMA (ecstasy) makes recalling favorite autobiographical memories feel more vivid, emotionally intense, and positive, while making recall of worst memories feel less negative. In a double-blind, placebo-controlled fMRI study with 19 participants who had prior MDMA experience, 100 mg of MDMA altered brain activity during memory recall: it increased activation in the fusiform gyrus and somatosensory cortex for favorite memories and decreased activation in the left anterior temporal cortex for worst memories. These neural changes suggest MDMA creates a positive emotional bias, which may explain why it helps patients revisit traumatic memories during psychotherapy for PTSD.
International Review of Psychiatry
July 4, 2018
Frederick S. Barrett, Katrin H. Preller, Mendel Kaelen
85 citations
Music listening has been used consistently from the beginning of therapeutic psychedelic research to guide experiences during the acute effects of psychedelic drugs. Recent findings indicate that music can support meaning-making, emotionality, and mental imagery after psychedelic administration, and suggest it plays an important role in facilitating positive clinical outcomes. This review examines the history, current research, and future directions of music in psychedelic therapy, arguing for more detailed and rigorous investigation into music's contribution to treating psychiatric disorders within this novel framework.
Neuropharmacology
November 20, 2017
Christopher Timmermann, Meg J. Spriggs, Mendel Kaelen et al.
83 citations
LSD reduces the brain's automatic neural adaptation to familiar sounds and blunts the neural 'surprise' response to unexpected sounds. Using magnetoencephalography and dynamic causal modeling, the authors found that LSD modulates backward (top-down) connectivity within a fronto-temporal network and intrinsic connectivity in the primary auditory cortex. These patterns resemble those seen in schizophrenia, ketamine states, and reduced consciousness, suggesting that backward connectivity may reflect altered perceptual learning common to multiple altered states rather than a direct marker of conscious level. The findings challenge top-down hypotheses of consciousness and indicate that several altered states may share this biophysical mechanism.
J Psychopharmacol
August 1, 2022
Victoria Amalie Nygart, Lis Marie Pommerencke, Eline Haijen et al.
73 citations
Depressive symptoms decreased two and four weeks after a psychedelic experience in a naturalistic, non-clinical setting. The study tracked a large group of people who planned to use psychedelics outside a lab or clinic, including only those with depressive symptoms at the start. A medicinal motive, prior psychedelic use, drug dose, and having an emotional breakthrough during the experience were all linked to greater symptom reductions. The authors note potential sample and attrition biases and call for further controlled and observational studies to confirm the findings.
Frontiers in Psychiatry
June 29, 2021
Keri Mans, Hannes Kettner, David Erritzøe et al.
65 citations
Psychedelic substances like LSD and psilocybin have regained legitimacy in clinical research. In this naturalistic observational study of volunteers intending to take a psychedelic, well-being was assessed using fourteen measures at four time points: 1 week before and 2 weeks, 4 weeks, and 2 years after the experience (sample sizes 654, 315, 212, and 64, respectively). Changes clustered into three factors: 'Being well,' 'Staying well,' and 'Spirituality.' Repeated measures analysis showed improvements in Being Well and Staying Well in the weeks following the experience, and mixed model analyses indicated these improvements remained statistically significant up to 2 years, despite high attrition. Spirituality did not show significant change.
Hum Brain Mapp
April 29, 2016
Leor Roseman, Martin I. Sereno, Robert Leech et al.
63 citations
Under LSD, with eyes closed, patches of the visual cortex that represent the same part of the visual field (e.g., both representing the horizontal meridian) showed stronger functional connectivity than patches representing different parts, compared to placebo. This pattern, measured in 10 healthy subjects using resting-state fMRI, suggests that the early visual system during LSD-induced imagery behaves as if it were processing actual visual input, even when no external visual stimuli are present.
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.
Language Cognition and Neuroscience
August 11, 2016
Neiloufar Family, David Vinson, Gabriella Vigliocco et al.
53 citations
LSD alters cognition by expanding the breadth of semantic activation. In a picture-naming task with ten participants, LSD reduced accuracy and altered error correction patterns compared to placebo, consistent with an increased spread of semantic activation. These effects align with a generalized entropic effect on the mind. The authors recommend future studies include direct neuroimaging and more naturalistic measures of semantic processing.
Neuropsychologia
April 5, 2016
Devin B. Terhune, David P. Luke, Mendel Kaelen et al.
45 citations
Lysergic acid diethylamide (LSD) induces synaesthesia-like experiences in non-synaesthetes, but these experiences do not meet two key criteria for genuine synaesthesia: consistency of stimulus-colour associations over time and inducer specificity. In a placebo-controlled pilot study, participants reported more spontaneous synaesthesia-like experiences under LSD compared to placebo, yet their colour responses to standardized graphemes and sounds did not differ across conditions in consistency or specificity. Individual differences in absorption propensity were linked to some effects. The findings suggest that LSD-induced synaesthesia-like experiences are not equivalent to genuine synaesthesia.
bioRxiv (Cold Spring Harbor Laboratory)
November 2, 2020
Pedro A. M. Mediano, Fernando E. Rosas, Christopher Timmermann et al.
39 citations
preprint
Psychedelics reliably increase brain entropy (neural signal diversity), an effect linked to psychological changes and opposite to the decrease seen during loss of consciousness. This study investigated how context—specifically stimulus manipulation—modulates that entropy increase. Participants under LSD or placebo experienced eyes-closed versus eyes-open conditions, or no stimulus, music, or video. Brain entropy rose with LSD across all conditions but was largest with eyes closed. Entropy changes consistently matched subjective ratings of the psychedelic experience, except during video viewing, suggesting competition between external stimuli and internal LSD-induced imagery. The findings provide quantitative evidence that context shapes neural dynamics during psychedelic experiences, supporting the practice of eyes-closed psychedelic psychotherapy, and challenge simplistic views of brain entropy as a direct measure of conscious level.