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.
Journal of Psychopharmacology
November 25, 2009
Celia J. A. Morgan, Leslie Muetzelfeldt, Mark Muetzelfeldt et al.
80 citations
A survey of 1501 UK residents with direct experience of 20 psychoactive substances asked them to rate each drug's physical, dependence-related, and social harms as well as benefits using the same scale previously used by experts. Users' harm rankings correlated very highly with expert rankings (r = 0.896). Alcohol, solvents, and tobacco were rated among the top ten most harmful drugs despite being unclassified under the Misuse of Drugs Act. No correlation existed between the legal classification of drugs and users' harm rankings. Ecstasy, cannabis, and LSD were rated highest by users for both acute and chronic benefits, suggesting users are relatively well informed and that the current legal classification does not inform users about harms.
Frontiers in Psychiatry
October 20, 2021
Meg J. Spriggs, Hannah Douglass, Rebecca J. Park et al.
78 citations
Anorexia nervosa is a severe psychiatric condition with few approved treatments. This paper describes how individuals with lived experience of anorexia nervosa helped shape a pilot study of psilocybin-assisted therapy through two online focus groups involving eleven people, and presents the protocol for that study at Imperial College London. Twenty female participants aged 21–65 with a body mass index of 15 kg/m² or above will receive three oral doses of psilocybin (up to 25 mg) over six weeks, supported by psychological preparation and integration, with a 12-month remote follow-up.
Neuropharmacology
September 27, 2022
David Nutt, Meg J. Spriggs, David Erritzøe
77 citations
Psychedelic therapy represents a promising new direction in psychiatry, offering effective treatment where conventional methods have failed and challenging the current diagnosis-specific model by showing transdiagnostic benefits. This has spurred significant investment and the creation of many new pharmaceutical companies researching known psychedelics and developing novel molecules. However, the authors caution that this enthusiasm must be grounded in established facts and current knowledge. They outline a knowledge framework that all innovative researchers in this field should consider to ensure rigorous and responsible scientific progress.
Psychological Medicine
June 1, 2024
Balázs Szigeti, Brandon Weiss, Fernando E. Rosas et al.
74 citations
In a double-blind trial comparing escitalopram and COMP360 psilocybin for major depressive disorder, patients held higher expectations for psilocybin than for escitalopram. Higher pre-trial expectancy for escitalopram predicted better outcomes with escitalopram, but expectancy for psilocybin did not predict response to psilocybin. Pre-treatment trait suggestibility was linked to therapeutic response in the psilocybin arm but not the escitalopram arm. These findings suggest that psychedelic therapy may be less influenced by expectancy biases than previously thought, and that highly suggestible individuals may be especially responsive to psilocybin treatment.
Neuropsychopharmacology
March 5, 2015
Sarah A. Stuart, Paul Butler, Marcus R. Munafò et al.
73 citations
Antidepressant drugs like ketamine and venlafaxine modify emotional biases in rats, but through different brain regions and at different times. In a bowl-digging task, rats learned two equal-value experiences, one under an affective manipulation and one under control conditions; their later choices revealed an affective bias. Ketamine, which acts rapidly, reduced a previously acquired negative bias when given before the preference test, and its effect depended on the medial prefrontal cortex. Venlafaxine, which acts slowly, induced a positive bias when given before learning, and its effect depended on the amygdala. Increasing the number of substrate-reinforcer associations amplified both positive and negative biases. This pattern may explain why venlafaxine has a delayed onset of action while ketamine acts quickly but lacks long-term efficacy.
The International Journal of Neuropsychopharmacology
August 30, 2017
Tom P. Freeman, Rebecca Pope, Matthew B. Wall et al.
67 citations
Cannabis dampens the brain's response to music in regions involved in reward and emotion, including the auditory cortex, hippocampus, amygdala, and ventral striatum. However, when cannabis also contains cannabidiol, these dampening effects are offset, and brain activity does not differ from placebo. Despite reduced neural responses, both types of cannabis increased participants' self-reported desire to listen to music and enhanced sound perception. The findings suggest that cannabidiol may mitigate some of cannabis's effects on brain reward systems.
Neuroimage
June 24, 2019
Carla Pallavicini, Martina G. Vilas, Mirta Villarreal et al.
66 citations
Classic serotonergic psychedelics and dissociative drugs like ketamine produce overlapping subjective effects despite different pharmacological mechanisms. Using source-localized magnetoencephalography, researchers found that LSD, psilocybin, and ketamine all caused widespread broadband reductions in spectral power. Machine learning classifiers trained on one pair of drugs could identify the third, confirming similarity. Functional connectivity analysis revealed decreases in low alpha and theta bands specific to LSD and psilocybin, linked to 5-HT2A agonism, while low beta band decreases were common to all three drugs. These findings quantify shared large-scale brain activity patterns across drug classes and suggest that beta band decoupling is an effect shared between NMDA antagonists and 5-HT2A agonists.
Acta Neuropsychiatrica
May 20, 2019
Oskar Hougaard Jefsen, Kristoffer Højgaard, Sofie Laage Christiansen et al.
66 citations
Psilocybin, a serotonin receptor agonist being studied for treatment-resistant depression, showed no antidepressant-like effect in a rat model of depression. In Flinders Sensitive Line rats, which model depression, neither psilocybin nor its active form psilocin reduced immobility time in the forced swim test, a standard measure of antidepressant activity. The drugs also did not alter locomotor activity in an open field test, ruling out stimulant effects. The rats bred to be depression-prone did show more immobility than their control counterparts, confirming the model's validity. The findings suggest that different animal models and behavioral tests may better translate the positive effects of psilocybin observed in humans.
PLoS Biology
January 27, 2015
David Nutt
66 citations
The United Nations drug control conventions from 1960 and 1971, along with later additions, have inadvertently created major restrictions on medical and life sciences research. These conventions need revision to allow neuroscience to advance without hindrance and to support innovation in treatments for brain disorders. In the interim, local changes like the United Kingdom reclassifying cannabis from Schedule 1 to Schedule 2 should be implemented to enable appropriate medical research development.
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.
Journal of Psychopharmacology
September 2, 2011
Paul Stokes, Alice Egerton, Ben Watson et al.
62 citations
Cannabis use during adolescence is considered a risk factor for psychosis, and animal studies indicate that THC, the psychoactive component, alters striatal dopamine transmission. This study compared striatal dopamine D2/D3 receptor availability in ten volunteers with a history of cannabis use and ten controls using PET scans. No significant differences in receptor availability were found between groups, nor any correlation with lifetime cannabis use frequency. However, limbic striatal receptor availability was ten percent lower in current nicotine smokers. These results suggest that, unlike other drugs of abuse, a history of cannabis use is not associated with changes in striatal dopamine D2/D3 receptor availability.
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.
BJPsych Open
September 1, 2022
Tommaso Barba, Sarah Buehler, Hannes Kettner et al.
57 citations
Psilocybin, but not the antidepressant escitalopram, reduced rumination and thought suppression in people with major depressive disorder six weeks after treatment. In a randomized trial of 59 participants, only those given psilocybin showed significant decreases in both maladaptive coping strategies. Among treatment responders, thought suppression decreased exclusively in psilocybin responders, while rumination decreased in both psilocybin and escitalopram responders. Reductions in rumination and thought suppression correlated with ego dissolution and psychological insight during psilocybin sessions, suggesting distinct therapeutic mechanisms for the two treatments.
J Affect Disord
April 1, 2018
Facundo Carrillo, Mariano Sigman, Diego Fernández Slezak et al.
57 citations
An algorithm analyzing natural speech from baseline interviews can predict which patients with treatment-resistant depression will respond to psilocybin therapy. The approach uses vocal patterns and linguistic features to forecast treatment outcomes, suggesting that speech biomarkers may enable personalized medicine in mental health. This predictive capability could help identify likely responders before treatment begins, advancing precision psychiatry for depression.
BMJ Case Rep
July 15, 2019
Ben Sessa, Chloe Sakal, Steve O’Brien et al.
55 citations
In a preliminary safety study of MDMA-assisted psychotherapy for alcohol use disorder, the first four participants tolerated the treatment without serious adverse events. The combination of MDMA with psychotherapy was feasible and acceptable, though the small number of participants limits conclusions about efficacy. These early results suggest that further research into this approach for alcohol dependence is warranted.
J Psychopharmacol
April 22, 2021
Robin 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.
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.
Journal of Psychopharmacology
April 15, 2010
Ben Sessa, Amanda Feilding, Robin Carhart-Harris et al.
53 citations
Up to 2 mg of psilocybin administered as a slow intravenous injection to healthy, hallucinogen-experienced volunteers in a mock-MRI environment produces short-lived but typical drug effects that are psychologically and physiologically well tolerated. The pilot work supports the viability of using functional magnetic resonance imaging to investigate psilocybin's effects on cerebral blood flow and activity.
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.
EClinicalMedicine
September 23, 2024
David Erritzøe, Tommaso Barba, Kyle T. Greenway et al.
46 citations
In a clinical trial, psilocybin therapy showed comparable effectiveness to a common SSRI antidepressant for treating depression, with both treatments leading to significant reductions in depressive symptoms over a follow-up period. The findings suggest psilocybin may offer a viable alternative to standard antidepressant medication, though the study's design and sample size limit the strength of conclusions.
Neuropsychologia
April 5, 2016
Devin B. Terhune, David 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.
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.
Frontiers in Psychology
April 4, 2014
Robin Carhart-Harris, David Nutt
42 citations
A commentary argues that dreaming is not a unique state of consciousness but rather a form of imaginative experience that shares core features with waking imagination. The author contends that dreams and waking fantasies are both products of the same cognitive processes, specifically the default mode network and memory consolidation mechanisms. The piece suggests that the vividness and narrative structure of dreams arise from the same neural dynamics that generate daydreams and creative thought, challenging the traditional view of dreaming as a separate or altered state of consciousness.
Journal of psychopharmacology (Oxford, England)
January 1, 2024
Lisa 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.