Psychopharmacology
September 2, 2016
Will Lawn, Tom P. Freeman, Rebecca Pope et al.
177 citations
Cannabis containing only THC reduced the likelihood of choosing high-effort rewards compared to placebo, indicating a transient amotivational state, while adding CBD altered the effect of THC on expected value. Cannabis-dependent individuals showed preserved motivation but impaired reward learning compared to non-dependent controls, though depression may have influenced results.
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.
Lancet Psychiatry
April 5, 2017
Ilina Singh, Celia Morgan, Valerie Curran et al.
158 citations
Based on current evidence, off-label ketamine use for severe, treatment-resistant depression does not violate ethical principles, but clinicians and professional bodies must establish guidelines for good practice, register all trial data, and continuously monitor risks. The analysis reviews evidence for ketamine's antidepressant effects and safety profile, concluding with recommendations for oversight bodies to support safe, effective, and ethical treatment.
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.
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.
Neuropharmacology
October 14, 2022
Ian Campbell, Ioanna A. Vamvakopoulou, Kelly A.d. Narine et al.
97 citations
Mescaline's pharmacological mechanisms resemble those of other classical psychedelics such as psilocybin and LSD. Consumption appears safe, with most intoxications being mild and easily treatable. The substance may offer clinical benefits, including improvements in mental well-being and potential to help overcome alcoholism. This article is part of a special issue on psilocybin research.
Frontiers in Psychiatry
June 12, 2023
Rayyan Zafar, Maxim Siegel, Rebecca Harding et al.
95 citations
Psychedelic therapy is regaining scientific and medical interest, with growing evidence for its safety and efficacy in treating psychiatric disorders, including addiction. This review charts research on these interventions for addiction, starting with the socioeconomic impact of addiction and current treatment options. It examines historical studies from the mid-late 1900s, real-world evidence from naturalistic and survey-based studies, and modern clinical trials from first-in-human to phase II. The review also covers translational neuropsychopharmacology techniques like fMRI and PET that help explain therapeutic mechanisms. A better understanding of these treatment effects can optimize psychedelic therapy development and improve patient outcomes.
Journal of Psychopharmacology
April 23, 2019
Matthew B. Wall, Rebecca Pope, Tom P. Freeman et al.
89 citations
Two strains of cannabis—one containing only THC (8 mg) and another containing THC plus CBD (8 mg THC + 10 mg CBD)—were compared with placebo in seventeen healthy, experienced but non-regular cannabis users. Using resting-state fMRI, both strains reduced functional connectivity in the default mode and salience networks relative to placebo, but with distinct spatial patterns. The THC-only strain specifically disrupted the posterior cingulate cortex within the default mode network, and this disruption correlated with subjective feelings of being 'stoned' and 'high'. The THC-plus-CBD strain produced less disruption of the salience network, suggesting CBD may buffer THC's effects on salience processing, which could underlie its potential therapeutic role in disorders like psychosis and addiction.
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 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.
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.
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.
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.
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.
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.