Neurosci Insights
October 8, 2024
Matthew B Wall, Rebecca Harding, Natalie Ertl et al.
3 citations
Psychedelic therapies are new psychiatric treatments that may need to be combined with existing medications, but little is known about their interactions with common psychiatric drugs. This commentary reviews key findings on such drug-drug interactions and proposes that multimodal neuroimaging, combining PET and fMRI with other measures, offers the most thorough way to study these interactions across molecular, functional, and clinical levels.
June 30, 2022
Matthew B. Wall, Rebecca Harding, Rayyan Zafar et al.
3 citations
preprint
Psychedelic therapy shows potential for treating psychiatric disorders like depression, addiction, and PTSD. Classic serotonergic psychedelics such as psilocybin, LSD, DMT, and 5-MeO-DMT are the main focus, along with ketamine, MDMA, and ibogaine. The concurrent use of advanced neuroimaging methods, particularly PET and MRI, has allowed precise assessment of brain effects, benefiting the development of these treatments. The text identifies gaps in knowledge that future multimodal imaging studies could address, providing a stronger foundation for psychedelic therapy.
PsyArXiv
May 24, 2022
Balázs Szigeti, David Nutt, Robin Carhart-Harris et al.
3 citations
preprint
Blinding in medical trials is meant to distribute expectancy effects evenly across treatment arms, but it often fails. Using computational modeling, this work shows that weak blinding combined with positive treatment expectancy can create an 'activated expectancy bias' (AEB), which inflates treatment effect estimates and can produce false positive findings. To address this, the authors introduce the Correct Guess Rate Curve (CGRC), a statistical tool that estimates what a perfectly blinded trial would have found from imperfectly blinded data. Re-analyzing a self-blinding psychedelic microdose trial, they find that observed placebo-microdose differences are susceptible to AEB and may be false positives, suggesting microdosing acts as an active placebo. The results underscore the difference between trials with a placebo control group and genuinely placebo-controlled trials.
European Neuropsychopharmacology
January 1, 2019
M. Madsen, Daniel Burmester, Dea Siggaard Stenbæk et al.
3 citations
No Summary
Neuroscience and biobehavioral reviews
July 1, 2026
Marcus J Glennon, Catherine I V Bird, Prateek Yadav et al.
2 citations
Setting up a psychedelic research study involves a long, arduous, and Kafkaesque process with many unstandardised challenges. These complexities challenge existing assumptions about psychiatric prescribing, the placebo effect, and definitions of selfhood. This review brings together major UK psychedelic research teams to formalise these unique considerations, addressing sociocultural, political, legal, pharmacological, safety, study design, and experiential facets. It identifies continuing areas of debate and provides a practical, experience-based guide with recommendations for policymakers and future researchers intending to set up a psychedelic study or clinical trial.
J Psychopharmacol
October 27, 2025
David J. Nutt, Celia Morgan, David Erritzøe et al.
2 citations
Ketamine, originally developed as an anesthetic, has emerged as a promising treatment for severe depression and other psychiatric conditions, particularly in patients who have not responded to traditional therapies. The compound can provide rapid relief from depressive symptoms, often within hours, which contrasts with conventional antidepressants that may take weeks to work. This surprising discovery has opened a new frontier in mental health treatment, offering hope for those with challenging mood disorders. However, the use of ketamine in psychiatry also raises concerns about its potential for abuse and long-term side effects, necessitating careful clinical oversight.
Research Square
August 22, 2025
Richard J. Zeifman, George Danias, Gabrielle Agin-Liebes et al.
2 citations
Psychedelics can acutely induce mystical experiences and elevated positive mood, which may contribute to the potential benefits of psychedelic therapy. However, there remains limited understanding of the occurrence and importance of specific positive emotional experiences within psychedelic therapy. Therefore, we examined the effects of psychedelics on positive emotional experiences and their association with improvements in mental health. Methods: Study 1 was an observational study of naturalistic psychedelic use. Study 2 used data from a clinical trial that compared psilocybin with escitalopram in individuals with major depressive disorder.
medRxiv
March 21, 2025
Jessica S. Henry, Bruna Giribaldi, David Nutt et al.
2 citations
preprint
In a randomized controlled trial of 59 patients with major depressive disorder, two high-dose psilocybin therapy sessions produced large increases in optimism and improvements in dysfunctional attitudes related to achievement, dependency, and self-control after six weeks. By contrast, a six-week daily course of escitalopram produced no change in optimism and only improved dysfunctional attitudes in the achievement domain. Psilocybin therapy was superior to escitalopram in remediating negative cognitive biases in depression.
Cureus
January 29, 2025
Sorcha O'Connor, Kate Godfrey, Sara Reed et al.
2 citations
The study aims to uncover the neural mechanisms by which psilocybin-assisted therapy affects obsessive-compulsive disorder (OCD) and whether those brain changes align with improvements in cognitive symptoms. A secondary goal is to test whether a low, tolerable dose is both practical and effective as a clinical treatment. The results will provide essential data for designing a future randomized controlled trial.
arXiv (Cornell University)
November 29, 2024
Claudio Agnorelli, Meg J. Spriggs, Kate Godfrey et al.
2 citations
Classic psychedelics (LSD, psilocybin, N,N-DMT) and non-classic psychedelics (ketamine, MDMA) enhance neuroplasticity, the nervous system's ability to adapt. Animal studies indicate these drugs induce meta-plasticity, heightening sensitivity to environmental stimuli, and hyper-plasticity, reopening developmental windows for long-term structural changes that affect mood and behavior. Translating these findings to humans is challenged by limitations in current imaging techniques, but emerging approaches like novel PET radioligands, non-invasive brain stimulation, and multimodal methods offer promising directions. This review informs development of targeted interventions for neuropsychiatric disorders and advances understanding of psychedelics' therapeutic potential.
Neuroscience applied
January 1, 2024
Drummond E-Wen Mcculloch, Juan Pablo Lopez, Christina Dalla et al.
2 citations
Classical psychedelic drugs like psilocybin and LSD stimulate the serotonin 2A receptor and are being investigated for clinical effects in brain disorders. Experts at the ECNP 'New Frontiers meeting' in March 2023 identified key knowledge gaps in psychedelic mechanisms, including the need for appropriate behavioral models, dose optimization, molecular mechanisms, sex differences, and effects on neurotransmitter release and brain activity. The meeting highlighted the importance of preclinical and neuroimaging research to address these gaps.
October 19, 2022
Stefan Baumann, Robin Carhart-Harris, David Nutt et al.
2 citations
preprint
In a placebo-controlled citizen science trial with 240 participants, microdosing tolerance was assessed by tracking whether correct guesses of receiving a microdose decreased with more doses taken. Correct guess probability declined overall, indicating tolerance developed. This tolerance was specific to LSD and LSD-analogue microdoses, not psilocybin microdoses. The findings suggest that microdosers may need to periodically suspend their routine to avoid tolerance and that psilocybin may be better suited for long-term protocols.
bioRxiv (Cold Spring Harbor Laboratory)
June 16, 2026
Paulina Clara Dagnino, Irene Acero-Pousa, Gorka Zamora‐lópez et al.
1 citation
Psilocybin and the conventional antidepressant escitalopram produce opposite changes in the brain's hierarchical non-equilibrium dynamics when treating major depressive disorder. Using resting-state fMRI before and after treatment, researchers built whole-brain models and measured how much each patient's brain activity deviated from the fluctuation-dissipation theorem. Baseline measures distinguished treatment responders from non-responders within each group. The deviation from the fluctuation-dissipation theorem may serve as a marker to differentiate the brain effects of psilocybin and escitalopram, contributing to understanding how these treatments work for depression.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
June 23, 2025
Jessica Henry, Bruna Giribaldi, David J Nutt et al.
1 citation
In patients with major depressive disorder, two high-dose psilocybin therapy sessions produced large increases in optimism and improvements in all three domains of dysfunctional attitudes (achievement, dependency, self-control) at six weeks, while a six-week daily course of escitalopram improved only the achievement domain and did not change optimism. Psilocybin also made patients more optimistic about desirable life events, whereas escitalopram reduced pessimism about negative life events. The findings suggest psilocybin therapy is superior to escitalopram for remediating negative cognitive biases in depression.
bioRxiv
February 8, 2025
Natalie Ertl, Imran Ashraf, Lisa Azizi et al.
1 citation
preprint
LSD and MDMA, two psychoactive drugs being explored for psychiatric use, alter how the striatum—a brain region central to reward and motivation—communicates with other areas. In a resting-state fMRI study, neither drug changed connectivity within the striatum's own networks. However, MDMA reduced connectivity between the limbic striatum and the amygdala, while LSD increased connectivity between the associative striatum and frontal, sensorimotor, and visual cortices. These changes occurred mostly outside standard striatal networks, suggesting the drugs reduce the brain's usual network segregation, which may help explain their therapeutic potential for conditions like addiction, mood disorders, and PTSD.
PsyArXiv
February 13, 2024
Michael Angyus, Sarah Osborn, Eline Haijen et al.
1 citation
preprint
A new 9-item scale called the Imperial Psychedelic Predictor Scale (IPPS) predicts key features of the acute psychedelic experience. Analyzing four independent datasets (two online surveys with 741 and 836 participants, and two controlled administration studies with 30 and 28 participants), the scale showed good internal consistency and three factors: set, rapport, and intention. The IPPS significantly predicted mystical, challenging, and emotional breakthrough experiences. In one controlled dataset, set and rapport explained 40% of variance in mystical experience, and set alone explained 16% of variance in challenging experience. In another, rapport explained 9% of variance in emotional breakthrough. The scale may improve safety and therapeutic outcomes by forecasting response variability.
Psychological Medicine
July 19, 2023
Brandon Weiss, Induni Ginige, Lu Shannon et al.
1 citation
No Summary
ChemRxiv
February 7, 2023
Vito F. Palmisano, Claudio Agnorelli, David Erritzøe et al.
1 citation
Classic psychedelics target the 5-HT2A serotonin receptor, but their precise mode of action remains unclear. Computational modeling of the receptor's orthosteric binding pocket for several psychedelics—including serotonin, LSD, DMT, and a photoswitchable analog (AzoDMT)—revealed two nearly equivalent binding poses. LSD and serotonin preferred the canonical crystallized pose, whereas DMT and 4-OH-DMT slightly favored a newly identified pose. The cis form of AzoDMT was the most stable, and its azobenzene domain interacted with the same residue (L229) responsible for LSD's extracellular loop closure. These simulations clarify drug–protein interactions and may aid development of new psychedelic compounds.
Neuroscience Applied
January 1, 2023
Hannah Douglass, Merle Spriggs, Kate Godfrey et al.
1 citation
No Summary
June 30, 2022
Sandeep M. Nayak, Bilal A. Bari, David B. Yaden et al.
1 citation
preprint
A Bayesian reanalysis of a trial comparing psilocybin (COMP360) to escitalopram for major depressive disorder found that psilocybin outperformed escitalopram, but not by a clinically meaningful amount. The analysis also found extremely strong evidence that psilocybin is non-inferior to escitalopram. Evidence for psilocybin's superiority varied by depression scale: indeterminate for one, strong for two, and extremely strong for another. For a clinically meaningful difference, evidence was moderate against it on one scale, indeterminate on two, and moderate supporting it on one. These results provide a more nuanced interpretation and support further research.
March 24, 2021
Pedro J. Teixeira, Matthew W. Johnson, Christopher Timmermann et al.
1 citation
preprint
Unhealthy behaviors like poor diet, inactivity, and smoking are major contributors to cancer, diabetes, and cardiovascular disease, causing substantial suffering and public health costs. Interventions to promote healthy behaviors increasingly draw on psychobiological models. This article explores the potential of psilocybin, a psychedelic with low toxicity and no addictive properties, to assist positive lifestyle change. Psilocybin has shown favorable effects in patients with depression, anxiety, and substance misuse, conditions marked by rigid behavioral patterns. The authors describe proposed mechanisms and research findings linking psychedelics to health behavior change, noting that therapeutic models combining psychedelic experiences with methods like Cognitive Behavior Therapy and Motivational Interviewing are already being tested for addiction and eating disorders. They suggest this research may extend to promoting diet, exercise, nature exposure, and mindfulness.
December 11, 2020
Balázs Szigeti, Laura Kärtner, Allan Blemings et al.
1 citation
A self-blinding citizen science study tested whether psychedelic microdosing improves well-being and cognition beyond placebo. 191 participants who already planned to microdose were randomly assigned to receive four weeks of microdoses, placebos, or a mix. All psychological outcomes—including well-being, mindfulness, and life satisfaction—improved from baseline in the microdose group, but the placebo group also improved, and no significant differences emerged between groups. Small acute differences in mood, energy, and creativity were observed, but these could be explained by participants correctly guessing whether they took a microdose. The findings suggest that the anecdotal benefits of microdosing are likely due to the placebo effect.
Br J Psychiatry
July 8, 2026
Hannah M. Douglass, Meg J. Spriggs, Kate Godfrey et al.
In a small pilot study, 21 women with anorexia nervosa received three doses of psilocybin (COMP360) over six weeks, combined with talk therapy and usual care. The treatment was well tolerated; common side effects were headache, nausea, and dizziness. Two serious adverse events (suicide attempts) occurred in one participant during the 6–12 month period. Eating disorder symptoms significantly improved at six months, and motivation to change improved at twelve months, though individual responses varied widely. The findings provide preliminary support for the feasibility and safety of psilocybin therapy in this population, but larger, more rigorous studies are needed.
bioRxiv (Cold Spring Harbor Laboratory)
June 26, 2026
Paulina Clara Dagnino, Irene Acero-Pousa, Robin Carhart‐Harris et al.
A central challenge in neuroscience is understanding how the human brain is organised to support optimal functioning and adaptability. One approach to characterise complex brain dynamics is by artificially perturbing whole-brain models. Here, we asked whether whole-brain organisation under perturbation in major depressive disorder (MDD) changes after intervention with psilocybin and escitalopram. First, we built whole-brain models of pre- and post-treatment resting-state functional magnetic resonance imaging (fMRI) and obtained an initial generative effective connectivity (GEC) matrix for each individual.
Research Square
June 19, 2026
Aline Frick, Grace Blest‐hopley, Manesh Grin et al.
In a reanalysis of a six-week randomized controlled trial comparing psilocybin with escitalopram for moderate-to-severe major depressive disorder, sex-related patterns emerged for anxiety and anhedonia. Women receiving psilocybin showed greater reductions in anxiety than men, while women receiving escitalopram showed greater reductions in anhedonia than men. For other depressive symptoms, thought suppression, and well-being, sex differences were small and uncertain. Sexual dysfunction severity was lower overall in the psilocybin group than in the escitalopram group and lower in women than in men, though the treatment-by-sex interaction was not significant. These preliminary findings suggest that responses to these serotonergic treatments may differ between women and men, supporting the need for adequately powered, sex-balanced trials.