Neuropharmacology
December 27, 2017
Leor Roseman, Lysia Demetriou, Matthew B. Wall et al.
239 citations
In an open-label study, 20 individuals with moderate to severe, treatment-resistant depression received two doses of psilocybin with psychological support. Nineteen completed fMRI scans before and after treatment. Depressive symptoms improved rapidly and enduringly. Right amygdala responses to fearful and happy faces increased after psilocybin, and increased responses to fearful versus neutral faces predicted clinical improvement at one week. This contrasts with SSRIs, which typically reduce amygdala responses, suggesting psilocybin may help patients confront and work through emotions rather than dampen them. The authors propose psilocybin with psychological support revives emotional responsiveness in depression.
The International Journal of Neuropsychopharmacology
October 21, 2022
James J Gattuso, Daniel Perkins, Simon Ruffell et al.
233 citations
Classical psychedelics like LSD, psilocybin, and ayahuasca consistently disrupt resting-state connectivity within the Default Mode Network (DMN) and increase functional connectivity between canonical resting-state networks. The DMN, a set of brain regions active during self-referencing and mind wandering, is altered in various neuropsychiatric conditions. While DMN modulation is central to some cognitive models of psychedelics, its role in their therapeutic potential remains unclear. This systematic review provides a comprehensive overview to guide future research on the neurocognitive mechanisms of these agents.
JAMA Psychiatry
February 1, 2021
David Nutt, Robin Carhart-Harris
233 citations
No Summary
Frontiers in Pharmacology
March 31, 2022
Roberta Murphy, Roberta Murphy, Hannes Kettner et al.
229 citations
In a trial comparing psilocybin-assisted therapy to escitalopram for moderate-to-severe depression, a stronger therapeutic alliance with the therapist predicted greater emotional breakthrough and mystical-type experiences during psilocybin sessions, and these experiences in turn predicted larger reductions in depression symptoms six weeks after treatment. Emotional breakthrough during the first session strengthened the alliance before the second session, while a weaker alliance before the second session directly predicted higher depression scores at the endpoint, independent of the acute psychedelic experience. The findings suggest the therapeutic relationship plays a key role in shaping both the quality of the psychedelic experience and clinical outcomes.
Frontiers in Psychology
August 15, 2018
Christopher Timmermann, Leor Roseman, L. Williams et al.
228 citations
Near-death experiences (NDEs) share striking phenomenological similarities with the effects of the psychedelic drug DMT. In a placebo-controlled, within-subjects study, 13 healthy participants received DMT and placebo, then completed a standard NDE measure. DMT significantly increased NDE-like features compared to placebo. NDE scores were linked to DMT-induced ego-dissolution and mystical experiences, as well as baseline traits of absorption and delusional ideation. Nearly all NDE features overlapped between DMT-induced experiences and a matched group of actual NDE experiencers. These results indicate a remarkable similarity between the DMT state and NDEs, warranting further research.
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.
Journal of Psychopharmacology
January 16, 2020
Lea J. Mertens, Matthew B. Wall, Leor Roseman et al.
211 citations
After a single 25 mg dose of psilocybin, patients with treatment-resistant depression showed decreased functional connectivity between the ventromedial prefrontal cortex and the right amygdala while viewing faces, particularly fearful and neutral ones. This decrease was linked to lower rumination levels one week later. Increased connectivity between these regions and occipital-parietal cortices also emerged. The findings suggest psilocybin therapy may revive emotional responsiveness at both neural and psychological levels, offering a potential treatment mechanism. Placebo-controlled studies are needed to confirm these results.
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.
Biological Psychiatry
January 10, 2014
Robin Carhart-Harris, Kevin Murphy, Robert Leech et al.
182 citations
The medial temporal lobes (MTLs) are specifically involved in how MDMA works in the brain, though more research is needed to understand how the drug's characteristic subjective effects emerge from its modulation of spontaneous brain activity.
BJPsych Open
December 23, 2021
Zach Walsh, Özden Merve Mollaahmetoğlu, Joseph M. Rootman et al.
180 citations
A systematic review of 83 studies found that subanesthetic doses of ketamine produce rapid, short-lived antidepressant and anti-suicidal effects. Evidence for other psychiatric conditions is less robust but suggests similarly positive but transient benefits. The conclusions are tentative due to high risk of bias across the included studies. Optimal dosing, administration methods, and best forms of adjunctive psychotherapy require further investigation.
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 J. A. Morgan, Valerie H. 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.
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.
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.
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.
J Psychopharmacol
February 18, 2021
Ben Sessa, Laurie Higbed, Steve O’Brien et al.
123 citations
In a first study of its kind, 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy was found to be safe and tolerable for patients with alcohol use disorder. The treatment did not raise serious safety concerns and was well tolerated by participants, suggesting that this combined approach warrants further investigation as a potential therapy for alcohol addiction.
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.
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 G 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.
Elife
October 12, 2020
Andrea Alamia, Christopher Timmermann, David 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.