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Journal articleGoodwin GM, Aaronson ST, Alvarez O, et al., 2025,
The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression.
, J Affect Disord, Vol: 372, Pages: 523-532OBJECTIVE: To determine the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcome in treatment-resistant depression. METHODS: For treatment-resistant depression, 233 participants received a single dose of 25, 10, or 1 mg of COMP360 psilocybin (a proprietary, pharmaceutical-grade synthesized psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.) with psychological support. The resulting psychedelic experience (Five-Dimensional Altered States of Consciousness questionnaire [5D-ASC] and Emotional Breakthrough Inventory [EBI]) were measured. These proximal variables and outcome 3 weeks post-administration (change in Montgomery-Åsberg Depression Rating Scale [MADRS]) were explored using correlation analysis. RESULTS: The mean intensity of psychedelic effects was dose-related, but distributions of scores for different doses overlapped considerably. Depression response correlated with select aspects of the psychedelic experience overall and for individual doses. At the 25 mg dose, 5D-ASC dimensions Oceanic Boundlessness (Pearson correlation coefficient r = -0.508) and Visual Restructuralization (r = -0.516), and EBI (r = -0·637) were the variables with the strongest correlation to the Week 3 change from Baseline in MADRS score. LIMITATIONS: The existence of correlation does not establish causation and exploratory findings require further replication, preferably in larger independent samples. CONCLUSIONS: The intensity of psychedelic experience overlaps widely across doses and mitigates the risk of unblinding to dose. Correlations between psychedelic experience and outcome suggest specificity in psilocybin's mechanism of action. Quality and intensity of psychedelic experience may be a measure of pharmacodynamic effect and reveal an effective dose response phenomenon for single oral doses.
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Journal articleYaden DB, Graziosi M, Owen AM, et al., 2025,
A Field-Wide Review and Analysis of Study Materials Used in Psilocybin Trials: Assessment of Two Decades of Research
, Psychedelic Medicine, Vol: 3, Pages: 1-18, ISSN: 2831-4425 -
Journal articleNutt DJ, 2025,
Drug development in psychiatry: 50 years of failure and how to resuscitate it.
, Lancet Psychiatry, Vol: 12, Pages: 228-238The past 50 years have seen remarkable advances in the science of medicine. The pharmacological treatments of disorders such as hypertension, immune disorders, and cancer are fundamentally different from those used in the 1970s, and are now more often based on disorder-specific pathologies. The same cannot be said for psychiatric medicines: despite remarkable advances in neuroscience, very few innovative treatments have been developed in this field since the 1970s. For depression, schizophrenia, anxiety disorders, and ADHD, pharmacological classes of medicines discovered through serendipity in the 1950s are still used despite hundreds of billions of US dollars being spent on drug discovery attempts based on new neuroscience targets. This Personal View presents my opinion on the reasons innovation in psychiatric treatment has not progressed as well as in other disorders. As a researcher in the field, I offer suggestions as to how this situation must be rectified soon, as by most analyses mental illness is becoming a major health burden globally. Most of my evidence is referenced, but where I have unpublished knowledge gained from consulting with pharmaceutical companies, it is presented as an opinion.
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Journal articleBrouwer A, Brown JK, Erowid E, et al., 2025,
A qualitative analysis of the psychedelic mushroom come-up and come-down.
, Npj Ment Health Res, Vol: 4Psychedelic therapy has the potential to become a revolutionary and transdiagnostic mental health treatment, yielding enduring benefits that are often attributed to the experiences that coincide with peak psychedelic effects. However, there may be an underrecognized temporal structure to this process that helps explain why psychedelic and related altered states of consciousness can have an initially distressing but ultimately distress-resolving effect. Here we present a qualitative analysis of the self-reported 'come-up' or onset phase, and 'come-down' or falling phase, of the psychedelic experience. Focusing on psilocybin or psilocybin-containing mushroom experience reports submitted to Erowid.org, we use phenomenological, thematic content and word frequency analysis to show that the come-up is more often characterized by negatively valenced feeling states that resemble an acute stress reaction, while the come-down phase is more often characterized by positively valenced feeling states of the sort often observed following recovery from illness or resolution of stress. The therapeutic and theoretical relevance of these findings are discussed.
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Journal articleJones G, Lowe MX, Nayak S, et al., 2025,
Examining differences in the effects and contexts of naturalistic psilocybin use for White participants vs. Participants of Color: A longitudinal online survey study.
, J Affect Disord, Vol: 370, Pages: 54-61BACKGROUND: Psilocybin (a psychoactive compound found in "magic mushrooms" or "shrooms") has been gaining increased attention in research and popular culture as a number of clinical and observational studies have demonstrated that it may have potential for improving mental wellbeing. Relatedly, there has been a substantial uptick in naturalistic (e.g., real-world, non-clinical) psilocybin use in the United States. While a number of longitudinal studies have demonstrated that naturalistic psilocybin use is linked to positive mental health outcomes on average, few studies have examined how the effects of psilocybin and contexts for psilocybin use may differ for White populations compared to Populations of Color. OBJECTIVE: To examine differences in health outcomes, subjective effects, and contexts of naturalistic psilocybin use in White participants compared to Participants of Color. METHODS: This study used data from a large, online longitudinal study of individuals who planned to engage in naturalistic psilocybin use (N = 2833). We used mixed-effects models to assess whether race/ethnicity (White vs. Participant of Color) moderated associations between time (Time 2 [initial assessment point for longitudinal measures], Time 5 [2-4 weeks post-psilocybin experience, and Time 6 [2-3 months post-experience]) and outcomes related to mental health (depression, anxiety, spiritual wellbeing, cognitive flexibility, emotion regulation [expressive suppression + cognitive reappraisal]). We also used exploratory chi-squared tests to examine differences in contexts for psilocybin use as well as differences in subjective effects related to the psilocybin experience. RESULTS: Race/ethnicity moderated the associations between time for predicting spiritual wellbeing (beta = -1.8; 95 % CI [-3.4, -0.17]; p < 0.05), cognitive flexibility (beta = -1.5 [-2.7, -0.26]; p < 0.05), and emotion regulation
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Journal articleZeifman R, Spriggs M, Kettner H, et al., 2025,
From relaxed beliefs under psychedelics (REBUS) to revised beliefs after psychedelics (REBAS)
, Scientific Reports, Vol: 15, ISSN: 2045-2322Objectives: This was a cross sectional study aimed at describing chest x-ray findings among children hospitalised with clinically diagnosed severe pneumonia and hypoxaemia (SpO2<92%) in three tertiary facilities in Uganda.Methods: We studied chest x-rays of 375 children aged 28 days to 12 years enrolled into the Children’s Oxygen Administration Strategies Trial (COAST)(ISRCTN15622505). Radiologists blinded to the clinical findings reported chest x-rays using the standardized World Health Organization methodology for paediatric chest Xray reporting. We summarised clinical data and chest x-ray findings using descriptive statistics. Chi-square and proportion tests were used to compare proportions and quantile regression compared medians. Results: We found 172, (45.8%) children had radiological pneumonia, 136 (36.3%) normal chest radiographs while 123 (32.8%) non-pneumonia findings, the major one being cardiovascular abnormalities,106 (28.3%); 56 (14.9%) chest radiographs had both pneumonia and other abnormalities. There was no difference in the prevalence of radiological pneumonia, cardiovascular abnormalities, and mortality between the group with severe hypoxaemia (SpO2<80%) and that with mild hypoxaemia (SpO280 to <92%), (95% CI: -13.2,7.1, -6.1,15.9) and -37.2, 20.4) respectively. Conclusion: This study highlights a relatively high prevalence of cardiovascular abnormalities in children who fulfill the WHO clinical criteria for severe pneumonia and have hypoxaemia. We recommend that chest x-ray examinations be routinely done for all children in this population because information concerning cardiovascular and respiratory systems can be obtained in one sitting and guide management better. We hope that these findings can prompt discussions into refining the clinical criteria used to classify and manage pneumonia in children in limited resource settings.
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Journal articleAgnorelli C, Cinti A, Barillà G, et al., 2025,
Neurophysiological correlates of ketamine-induced dissociative state in bipolar disorder: insights from real-world clinical settings.
, Mol PsychiatryKetamine, a dissociative compound, shows promise in treating mood disorders, including treatment-resistant depression (TRD) and bipolar disorder (BD). Despite its therapeutic potential, the neurophysiological mechanisms underlying ketamine's effects are not fully understood. This study explored acute neurophysiological changes induced by subanesthetic doses of ketamine in BD patients with depression using electroencephalography (EEG) biomarkers. A cohort of 30 BD (F = 12) inpatients with TRD undergoing ketamine treatment was included in the study. EEG recordings were performed during one of the ketamine infusions with doses ranging from 0.5 to 1 mg/kg, and subjective effects were evaluated using the Clinician-Administered Dissociative States Scale (CADSS). Both rhythmic and arrhythmic features were extrapolated from the EEG signal. Patients who exhibited a clinical response to ketamine treatment within one week were classified as early responders (ER), whereas those who responded later were categorized as late responders (LR). Ketamine reduced low-frequency spectral power density while increasing gamma oscillatory power. Additionally, ketamine flattened the slope of the power spectra, indicating altered scale-free dynamics. Ketamine also increased brain signal entropy, particularly in high-frequency bands. Notably, LR exhibited greater EEG changes compared to ER, suggesting endophenotypic differences in treatment sensitivity. These findings provide valuable insights into the neurophysiological effects of ketamine in BD depression, highlighting the utility of EEG biomarkers for assessing ketamine's therapeutic mechanisms in real-world clinical settings. Understanding the neural correlates of ketamine response may contribute to personalized treatment approaches and improved management of mood disorders.
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Journal articleKettner H, 2025,
Observational cohort study of a group-based VR program to improve mental health and well-being in people with life-threatening illnesses
, Frontiers in Virtual Reality, ISSN: 2673-4192Introduction. Being diagnosed with a life-threatening illness (LTI) is often accompanied by feelings of fear, uncertainty, and loneliness that can severely impact mental health. Relatively few interventions are available to address the existential concerns of individuals facing LTI, while treatment of the underlying physical ailment typically remains the priority of the healthcare system. Research has shown that psychedelic-assisted psychotherapy (PAT) holds promise for supporting mental health in people with LTIs. However, PAT’s potential in this population remains curtailed by several limitations, including regulatory and accessibility issues. Novel approaches that could provide some of the benefits of psychedelic experiences, while avoiding associated challenges, would therefore be highly desirable for supporting the mental well-being of people with LTIs. Among such interventions, VR-based experiences have been suggested as a promising candidate. We here evaluate a program that includes weakly representational, multi-user VR experiences based on a design aesthetic previously described as “numadelic”, which has been demonstrated to elicit self-transcendent experiences comparable to psychedelics.Methods. A prospective cohort study design was used to assess the effects of “Clear Light” (CL) a group-based, 6-session multimedia program that included VR experiences, video calls, and text chats spanning 3 weeks. Participants were individuals suffering from LTIs that self-selected to participate in the CL program. A total of N=15 participants were evaluated based on assessments one week before and after the program, using self-report measures of anxiety, depression, well-being, and secondary psychological outcomes.Results. The intervention was well-tolerated among participants. Significant improvements with moderate effect sizes were observed on self-reported measures of anxiety, depression, and well-being. Secondary measures assessing demor
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Journal articleShinozuka K, Tewarie PKB, Luppi A, et al., 2025,
LSD flattens the hierarchy of directed information flow in fast whole-brain dynamics
, Imaging Neuroscience, Vol: 3<jats:title>Abstract</jats:title> <jats:p>Psychedelics are serotonergic drugs that profoundly alter consciousness, yet their neural mechanisms are not fully understood. A popular theory, RElaxed Beliefs Under pSychedelics (REBUS), posits that psychedelics flatten the hierarchy of information flow in the brain. Here, we investigate hierarchy based on the imbalance between sending and receiving brain signals, as determined by directed functional connectivity. We measure properties of directed functional hierarchy in a magnetoencephalography (MEG) dataset of 16 healthy human participants who were administered a psychedelic dose (75 micrograms, intravenous) of lysergic acid diethylamide (LSD) under four different conditions: eyes-closed with or without music and eyes-open with or without a video stimulus. Across the whole brain, LSD diminishes the asymmetry of directed connectivity when averaged across time. Additionally, we demonstrate that machine learning classifiers distinguish between LSD and placebo more accurately when trained on one of our hierarchy metrics than when trained on traditional measures of functional connectivity. Taken together, these results indicate that LSD weakens the hierarchy of directed connectivity in the brain by increasing the balance between senders and receivers of neural signals.</jats:p>
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Journal articleGodfrey K, Weiss B, Zhang X, et al., 2025,
An investigation of acute physiological and psychological moderators of psychedelic-induced personality change among healthy volunteers
, Neuroscience Applied, Vol: 4This study investigated the effects of a single high-dose of psilocybin on personality traits in psychedelic-naïve healthy volunteers. These data originate from a larger within-subjects fixed-order design trial, where a single high dose of psilocybin (25 mg) was administered in a psychologically supportive setting and was compared against a (one-month) prior, 1 mg ‘placebo’ dose. Personality shifts were assessed by the Big Five Inventory and the Big Five Aspect Scale, while the Altered States of Consciousness questionnaire (5D-ASC) and the Psychological Insight Scale gauged the acute psychological effects of the substance. Electroencephalography provided neurophysiological insights, specifically examining alpha power and Lempel-Ziv complexity (LZc). Results indicated significant reductions in neuroticism one month after 25 mg psilocybin administration, a finding consistent with prior studies. Reductions in neuroticism were moderated by the subjective meaningfulness of the psychedelic experience, as well as by the dread of ego dissolution subscale of the 5D-ASC, suggesting a relationship between acute drug effects and enduring personality alterations. Thus, this study substantiates the role of acute psychedelic states in catalysing lasting personality transformations in a generally beneficial direction, with broader implications for therapeutic applications and understanding of personality dynamics.
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