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.
International Journal of Environmental Research and Public Health
December 16, 2019
Hannes Kettner, Sam Gandy, Eline 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 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.
Scientific Reports
January 21, 2021
Laura Kaertner, Michael B. Steinborn, Hannes Kettner et al.
152 citations
A prospective study of weekly psychedelic microdosing found that participants reported improved well-being, emotional stability, and reduced anxiety and depressive symptoms over four weeks. However, baseline positive expectancy scores predicted these improvements, suggesting a significant placebo response. The findings caution against overinterpreting the therapeutic value of microdosing.
Proc Natl Acad Sci U S A
February 1, 2022
Daniel Toker, Ioannis Pappas, Janna D. Lendner et al.
148 citations
During conscious states, the cortex operates near a mathematically specific critical point called the edge-of-chaos, the boundary between stability and chaos. Applying a modified 0-1 chaos test to ECoG and MEG recordings from humans and macaques, evidence suggests that unconscious states—such as generalized seizure and anesthesia—involve a shift of low-frequency cortical oscillations away from this critical point, disrupting information processing. Psychedelic states tune these oscillations closer to the critical point, potentially increasing information richness. Analysis of clinical EEG from patients with disorders of consciousness indicates that measuring proximity to this critical point may serve as a clinical index of consciousness.
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.
Psychopharmacology
December 18, 2019
Neiloufar Family, Émeline L. Maillet, Luke T. J. Williams et al.
142 citations
Repeated low doses of LSD are safe and well tolerated in older adults. In a double-blind, placebo-controlled trial, 48 healthy volunteers aged around 63 received either 5, 10, or 20 micrograms of LSD or a placebo every four days for three weeks. LSD was undetectable in the blood at the 5 microgram dose, while peak levels for higher doses occurred within 30 minutes. Adverse events were no more frequent than with placebo, and tests of cognition, balance, and proprioception showed no impairment. These results support further clinical development of low-dose LSD for treating or preventing Alzheimer's disease.
Neuroimage
March 8, 2020
Manesh Girn, Caitlin Mills, Leor Roseman et al.
139 citations
Creativity involves alternating between generating ideas and evaluating them. A refined Dynamic Framework of Thought describes creative generation not as one mental state but as a product of many varying states. The psychedelic state is proposed as a mental state with high potential for facilitating creative generation, making psychedelic substances useful experimental tools for studying the neuroscience of creativity.
Curr Opin Psychiatry
January 1, 2019
Robin Carhart-Harris
138 citations
Psychedelics are reawakening interest in psychiatry and neuroscience due to promising small-scale clinical trials and brain imaging findings. This opinion piece proposes that psychedelics work through a cascade of neurobiological changes spanning multiple scales: from molecular serotonin 2A receptor agonism, to heightened anatomical and functional plasticity, increased brain entropy, and network-level disintegration and desegregation. These changes ultimately relax high-level beliefs, and psychedelic therapy aims to harness that belief-relaxation to revise pathological beliefs toward healthier ones.
J Psychopharmacol
January 5, 2022
Joseph Peill, Katie 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 Carhart-Harris, James 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.
Neuroimage
April 25, 2022
Manesh Girn, Leor Roseman, Boris C. Bernhardt et al.
112 citations
LSD and psilocybin flatten the brain's normal hierarchical organization, reducing the functional separation between sensory and higher-order networks and increasing cross-talk between them. Analyzing two resting-state fMRI datasets, the principal gradient of cortical connectivity—which normally runs from basic sensory areas to complex association regions—was significantly compressed under both drugs compared to placebo. This flattening was driven by decreased specialization at both ends of the hierarchy: default mode and frontoparietal networks at the top, and somatomotor networks at the bottom. The findings support a proposed mechanistic model of the psychedelic state and demonstrate that macroscale connectivity gradients can be acutely altered by a pharmacological intervention.
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.
Neuropharmacology
December 27, 2022
Robin Carhart-Harris, Shamil Chandaria, David Erritzøe et al.
106 citations
A theoretical model proposes that psychopathology arises from a defensive process called canalization, which narrows an individual's range of thoughts, feelings, and behaviors by increasing precision or reducing variance in neural responses. This contrasts with an early form of plasticity, TEMP (Temperature or Entropy Mediated Plasticity), which increases variance and learning rate. Canalization entrenches pathology as the agent develops expertise in their disorder, while TEMP, combined with gentle psychological support, may counter this entrenchment. The model distinguishes adaptive from maladaptive canalization and suggests concrete experiments to test its hypotheses.
Frontiers in Psychiatry
August 7, 2020
Richard J. Zeifman, Anne Catherine Wagner, Ros Watts et al.
104 citations
In two prospective studies with convenience samples of people planning to use a psychedelic (total N=358), participants completed questionnaires before use and at 2 and 4 weeks afterward. Across both studies, significant decreases occurred in experiential avoidance, depression severity, and suicidal ideation after psychedelic use. Decreases in experiential avoidance were significantly associated with decreases in depression severity and suicidal ideation. These results suggest that psychedelics may reduce experiential avoidance, depression severity, and suicidal ideation, and that reduced experiential avoidance may be a transdiagnostic mechanism in psychedelic therapy. Integrating psychedelics with therapies targeting experiential avoidance, such as acceptance and commitment therapy, may enhance outcomes.
Scientific Reports
September 25, 2023
Rebecka Bremler, Nancy Katati, Parvinder Shergill et al.
102 citations
Negative psychological responses to psychedelics lasting more than 72 hours are real and can include new psychiatric diagnoses or worsened symptoms. In a sample of 32 individuals who completed an online questionnaire, 37.5% received a new psychiatric diagnosis after their psychedelic experience, and 87% experienced anxiety symptoms. Deeper interviews with 15 of the most severe cases revealed potential causes: unsafe environments, unpleasant acute experiences, prior psychological vulnerabilities, high or unknown drug doses, and young age. The findings cannot estimate how common such harms are due to the small, selective sample and study design focused only on negative outcomes.
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.
Frontiers in Psychiatry
July 19, 2021
Rita Kočárová, Jiřı́ Horáček, Robin Carhart-Harris
95 citations
Psychedelic therapy may work across many psychiatric disorders by increasing neuronal and mental plasticity, which enhances the potential for change. Combined with psychotherapy, this plasticity can promote healthy adaptability and resilience, protecting long-term well-being. The authors propose that psychedelics' core action is transdiagnostic, offering prophylactic benefits beyond current treatments. They link candidate neurological and psychological markers to a predictive processing model, suggesting broad public health impact.
J Psychopharmacol
February 28, 2019
David Erritzøe, James Smith, Patrick M. Fisher et al.
95 citations
People who use psychedelics recreationally tend to score higher on the personality trait openness, which involves being open-minded, curious, and receptive to new experiences. This study examined whether this link might be explained by differences in the brain's serotonin system, a key chemical system affected by psychedelics. Using brain imaging, the researchers measured serotonin markers in recreational users and non-users. The findings suggest that higher openness in psychedelic users is not directly tied to these serotonin markers, indicating that other factors may underlie the personality differences.
Neuroimage
June 30, 2020
Thomas F. Varley, Robin Carhart-Harris, Leor Roseman et al.
91 citations
Psychedelic drugs like psilocybin and LSD increase the fractal dimension of brain activity, suggesting that the brain moves toward a critical state between order and disorder. Using fMRI data from volunteers, the study tested two fractal measures: one for functional connectivity networks and one for BOLD time-series. Both drugs significantly increased the fractal dimension of functional connectivity networks. LSD also significantly increased the fractal dimension of BOLD signals, while psilocybin showed a non-significant trend in the same direction. Changes in the fractal dimension of BOLD signals were localized to brain areas in the dorsal attention network. These results indicate that psychedelic-induced changes in consciousness are associated with evolution toward a critical zone.
The British Journal of Psychiatry
March 1, 2017
Matthew M. Nour, Robin Carhart-Harris
90 citations
Altered self-experiences, which occur in some psychiatric conditions and can be induced by psychoactive drugs or spiritual practices, are now being studied through a neuroscience framework that combines functional neuroimaging with altered states from psychedelic drugs. This emerging understanding may significantly benefit psychiatry.
Schizophrenia Bulletin
August 5, 2020
Pantelis Leptourgos, Martin Fortier-Davy, Robin Carhart-Harris et al.
88 citations
A multidisciplinary working group reviewed evidence on the similarities and differences between hallucinations induced by psychedelics and those occurring in schizophrenia-spectrum disorders, examining data from pharmacology, brain imaging, phenomenology, and anthropology. The authors highlight both shared features and distinct characteristics across these scales, and attempt to integrate findings using computational approaches. They conclude with recommendations for future research, emphasizing the need for further study to clarify the relationship between these types of hallucinations.
Neuroimage
December 17, 2019
Lionel Barnett, Suresh Muthukumaraswamy, Robin Carhart-Harris et al.
88 citations
The psychedelic state involves a breakdown in patterns of information flow in the brain. Using MEG recordings, researchers measured functional connectivity after administration of LSD, psilocybin, and low-dose ketamine, and compared them with the non-psychedelic drug tiagabine. All three psychedelics decreased directed functional connectivity (information flow) throughout the brain, as measured by Granger causality. For LSD, this decrease was coupled with an increase in undirected functional connectivity (correlation and coherence), a surprising opposite movement that highlights the importance of comparing multiple measures of functional connectivity in neuroimaging data.
Journal of Psychopharmacology
May 29, 2021
Pedro J. Teixeira, Matthew W. Johnson, Christopher Timmermann et al.
87 citations
Healthy behaviors like diet, exercise, and not smoking greatly reduce risks for cancer, diabetes, and cardiovascular disease, but lifestyle diseases remain a major burden. Psychedelic substances, particularly psilocybin, are being explored as tools to promote positive lifestyle change. Psilocybin has low toxicity, is non-addictive, and has shown favorable changes in patients with depression, anxiety, and substance misuse. The article describes proposed mechanisms of action and research linking psychedelics to health behavior change, suggesting that combining psychedelic experiences with methods like Cognitive Behaviour Therapy and Motivational Interviewing may help improve diet, exercise, nature exposure, and mindfulness.