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.
Neuropsychopharmacology
April 26, 2017
Robin L 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 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.
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.
Elife
March 2, 2021
Balázs Szigeti, Laura Kärtner, Allan Blemings et al.
192 citations
A self-blinding citizen science trial with 191 participants tested whether microdosing psychedelics produces psychological benefits beyond a placebo. All psychological outcomes improved from baseline to after the four-week dose period in the microdose group, but the placebo group also improved, and no significant between-group differences were observed. Small, significant differences in acute measures (emotional state, drug intensity, mood, energy, creativity) and post-acute anxiety appeared, but these could be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.
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.
J Psychopharmacol
January 5, 2022
Joseph M Peill, Katie E Trinci, Hannes Kettner et al.
135 citations
A new self-report questionnaire, the Psychological Insight Scale, was developed and validated to measure the degree of psychological insight people gain from a psychedelic experience. The scale was tested in a large online sample and showed strong reliability and validity, capturing a distinct aspect of psychedelic-induced change not measured by existing tools. Higher scores on the scale were associated with greater improvements in well-being and reductions in psychological distress, suggesting that psychological insight may be a key mechanism underlying the therapeutic potential of psychedelics.
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.
Elife
October 12, 2020
Andrea Alamia, Christopher Timmermann, David J Nutt et al.
86 citations
The psychedelic drug DMT rapidly induces a highly immersive state of consciousness with vivid visual imagery. In a study of participants who received DMT or placebo (saline) while keeping their eyes closed, brain electrical activity showed a pattern of cortical travelling waves similar to that normally seen during visual stimulation. The typical alpha-brainwave rhythms of eyes-closed rest were significantly reduced, while forward-directed waves from lower to higher brain regions increased. These findings support the idea that psychedelics reduce the brain's reliance on prior expectations, shifting the balance from top-down to bottom-up information processing, which may be a key mechanism underlying altered states of 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.
J Psychopharmacol
April 22, 2021
Robin L Carhart-Harris, Anne C Wagner, Manish Agrawal et al.
54 citations
Psychedelic therapy is experiencing a resurgence due to favorable regulations, policy changes, and positive trial results, but current confirmatory trials may not fully address safety and best practice. The authors recommend supplementing these trials with pragmatic trials, real-world data initiatives, and digital health solutions to discover optimal and personalized treatment protocols. These steps aim to develop safe, effective, and cost-efficient psychedelic therapy, which is susceptible to hype and regulatory challenges given its history.
J Psychopharmacol
March 4, 2024
Alessia Marrocu, Hannes Kettner, Brandon Weiss et al.
51 citations
About 16% of people who used psychedelics in naturalistic settings showed a clinically meaningful decline in psychological well-being four weeks later. Those with a prior diagnosis of a personality disorder were disproportionately affected: 31% were negative responders, and multivariate regression indicated a greater than four-fold elevated risk of adverse psychological responses. The findings suggest that personality disorders may represent an elevated risk for psychedelic use, and that psychological support and a good therapeutic alliance may be especially important for this population.
Neuropsychopharmacology
February 14, 2017
Ishan C Walpola, Timothy Nest, Leor Roseman et al.
50 citations
MDMA (100 mg) reduces functional connectivity between the right insula and the salience network in the brain, indicating a disintegration of this network. This decrease in connectivity correlates with higher baseline trait anxiety and more intense acute experiences of altered bodily sensations under the drug. The findings suggest that insular disintegration is a neurobiological signature of the MDMA experience, linking the drug's effects on brain activity to individual differences in anxiety and bodily awareness.
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 Erritzøe 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.
J Psychopharmacol
June 15, 2020
Anna Borissova, Bart Ferguson, Matthew B Wall et al.
37 citations
MDMA did not increase prosocial behavior in a controlled laboratory setting, despite raising blood levels of the drug and self-reported feelings of closeness and euphoria. In a double-blind, placebo-controlled experiment with 20 healthy volunteers, MDMA (100 mg) failed to significantly change task-based measures of empathy, trust, or cooperative behavior compared to placebo. Bayesian analyses supported the conclusion that MDMA and placebo had equivalent effects on empathy and cooperation. The drug also did not alter mood three days after administration. These findings suggest that the acute prosocial effects of MDMA observed in naturalistic or therapeutic contexts may not replicate under controlled experimental conditions.