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Journal articleGoodwin GM, Aaronson ST, Alvarez O, et al., 2026,
The role of therapeutic alliance in psilocybin treatment for treatment-resistant depression: A post hoc path analysis.
, J Affect Disord, Vol: 406INTRODUCTION: The contribution of patient support to psilocybin's antidepressant effects remains uncertain. METHODS: Relationships between therapeutic alliance (Scale to Assess Therapeutic Relationship-Patient version; STAR-P), psychedelic experience (Five-Dimensional Altered States of Consciousness Questionnaire and Emotional Breakthrough Inventory; 5D-ASC and EBI) and clinical outcomes (Montgomery-Åsberg Depression Rating Scale; MADRS) were explored using correlation and path analysis for individuals with treatment-resistant depression receiving 25 mg psilocybin with monitoring and support (N = 79). RESULTS: Change from Baseline to Week 3 MADRS scores showed weaker correlations with pre-dosing therapeutic alliance (-0.178) than with measures of the psychedelic experience: EBI (-0.637), Oceanic Boundlessness (-0.508), and Visual Restructuralization (-0.516). Path analysis showed no nominally significant direct effects of therapeutic alliance on Week 3 MADRS scores, but there were nominally significant effects of therapeutic alliance on psychedelic experience (Oceanic Boundlessness (β = 0.28), Visual Restructuralization (β = 0.27), and Auditory Alterations (β = 0.25)). Only one indirect effect of therapeutic alliance on clinical outcome reached nominal significance (via Visual Restructuralization; β = -0.15). Stronger effects were seen on clinical outcomes for psychedelic experience (EBI (β = -0.59), Oceanic Boundlessness (β = -0.53), Visual Restructuralization (β = -0.54), and Auditory Alterations (β = -0.24)). CONCLUSIONS: The therapeutic alliance appeared to facilitate the psychedelic experience, and these experiences in turn had stronger nominally significant direct effects on clinical outcomes. The effects of the alliance itself on therapeutic efficacy were either limited or absent. TRIAL REGISTRATION: EudraCT number: 2017
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Journal articleAday JS, Carhart-Harris RL, Boehnke KF, 2026,
Blunted Psychedelic Drug Effects in Older Adults.
, Am J Geriatr Psychiatry, Vol: 34, Pages: 873-876 -
Journal articleGirn M, Doss MK, Roseman L, et al., 2026,
An international mega-analysis of psychedelic drug effects on brain circuit function.
, Nat MedPsychedelic drugs are re-emerging as promising scientific and clinical tools. However, despite a rapidly expanding literature on their therapeutic value, the neural mechanisms underlying psychedelic effects remain unclear. Resting-state functional magnetic resonance imaging studies of acute psychedelic effects, conducted independently by several research groups, have so far yielded fragmented and sometimes inconsistent findings. Here, to help facilitate greater convergence, we conducted a 'mega-analysis' integrating 11 independent resting-state functional magnetic resonance imaging datasets across five psychedelic drugs (psilocybin, lysergic acid diethylamide, mescaline, N,N-dimethyltryptamine and ayahuasca) from research groups spanning three continents and five countries. By applying a uniform preprocessing pipeline and a Bayesian hierarchical modeling framework, we discovered several common features in the induced alterations to brain function across drugs and sites. Most prominently, we identified a core signature of increased functional connectivity between transmodal (default, frontoparietal and limbic) and unimodal networks (visual and somatomotor), with subnetwork specificity. Furthermore, key subcortical regions (thalamus, caudate and putamen) and the cerebellum exhibited altered coupling with sensorimotor networks. In contrast to several single-site reports, Bayesian modeling revealed weak-to-moderate and selective reductions in within-network functional connectivity, with substantial variability across drugs and networks. Together, these findings extend past work by demonstrating that psychedelics reconfigure large-scale cortical organization while selectively engaging subcortical circuitry. This study provides the most comprehensive synthesis of psychedelic brain action to date, helping resolve inconsistencies and offering a probabilistic map of how psychedelics alter large-scale brain organization. We hereby provide a cornerstone to benchmark and shephe
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Journal articleNewson M, Roseman L, Haslam SA, 2026,
Towards social curative psychedelic treatment.
, Discov Ment Health -
Journal articleAgnorelli C, Peill J, Sawicka G, et al., 2026,
Detecting neuroplastic effects induced by ketamine in healthy human subjects: A multimodal approach.
, J Cereb Blood Flow MetabWe investigated ketamine's neuroplastic effects in healthy human subjects using integrated Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) measures before and 1-8 days after a single psychedelic dose of ketamine (1 mg/kg, intravenous). Eleven male participants underwent two PET/MRI scans with [11C]-UCBJ (synaptic density/plasticity), 1H-MRS (glutamate and GABA) and resting-state fMRI (intrinsic brain activity, functional connectivity), before and after ketamine. While group-level analyses showed no significant increases in PET synaptic markers, ketamine administration resulted in significantly elevated glutamate levels within the anterior cingulate cortex (ACC). Functional connectivity analyses revealed reduced coupling between the ACC and the dorsolateral prefrontal cortex (dlPFC) and increased coupling between the ACC and the amygdala in the days following ketamine administration. Our multimodal analysis revealed that participants showing an increase in [11C]-UCBJ volume distribution (VT), a putative index of synaptic plasticity, showed a correlated reduction in intrinsic activity within regions belonging to the default mode network (DMN). By linking molecular, cellular and network-level changes, our results point to the DMN as a central hub where ketamine may reshape brain hierarchies in the long term, providing new directions for understanding its therapeutic mechanisms and developing targeted treatments.
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Journal articleAgnorelli C, Garling HD, Paterson LM, et al., 2026,
Recent advances in PET measures of brain 5-HT release.
, J Cereb Blood Flow MetabSerotonin (5-hydroxytryptamine, 5-HT) is a neuromodulator underpinning various psychological and physiological processes, with dysregulation implicated in numerous psychiatric disorders. Non-invasive measurement of endogenous 5-HT release in the living human brain is essential to advance understanding of the serotonergic system. The combination of Positron Emission Tomography (PET) neuroimaging of serotonergic receptors with pharmacological and behavioural challenges that stimulate endogenous 5-HT release, offers a unique approach to quantify 5-HT dynamics in vivo. In 2010, Paterson and colleagues concluded in a thorough review that measures of 5-HT release were constrained by limitations in the sensitivity of available tracers and potency of pharmacological challenges. Novel tracers combined with optimised pharmacological challenge paradigms have demonstrated sensitivity to changes in endogenous 5-HT, enabling reproducible detection of acute 5-HT release in both preclinical and human studies in the last 15 years of research. These include the use of agonist radioligands with preferential binding to high-affinity receptor states, such as [11C]AZ10419369 and [11C]Cimbi-36, antagonist tracers, such as [18F]Altanserin, refined challenge designs using pharmacological 5-HT releasers, such as fenfluramine and amphetamine, and the integration of hybrid PET/MR imaging to assess neurovascular aspects. These advances have shifted the field from questioning feasibility to addressing optimal strategies for measuring serotonergic dynamics.
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Journal articleFabiano N, Stubbs B, Lawrence DW, et al., 2026,
The combination of exercise and psychedelics for the treatment of major depressive disorder.
, Discov Ment Health, Vol: 6Upwards of 50% of people do not respond to the primary treatment modalities for major depressive disorder (MDD), which has led to increased attention and use of alternative methods, including exercise and psychedelics. While interventions using either exercise or psychedelics have demonstrated largely positive results in isolation, their synergistic potential has yet to be explored. As such, this commentary provides an overview of exercise/psychedelics as a treatment for depression and their potential synergy and/or complementarity. From a biological perspective, psychedelics acutely enhance brain-derived neurotrophic factor (BDNF) signalling, while exercise provides sustained BDNF elevation; psychedelics enhance neuroplasticity largely in the cortex (with only modest effects in the hippocampus), while exercise boosts hippocampal neurogenesis; psychedelics increase glutamate release via stimulation of 5-HT2A receptors on pyramidal neurons, while exercise enhances glutamatergic transmission via the endocannabinoid system and reduction of systemic inflammation; both boost serotonin release; and psychedelics temporarily disrupt functional connectivity between the hippocampus and default mode network (DMN), while exercise normalizes this connectivity, which may sustain post-psychedelic gains. Through the lens of psychological and behaviour change, psychedelics appear to facilitate the adoption or maintenance of physical activity habits, increase psychological flexibility, and since exercise is associated with emotional resilience to acute stress, this may allow users to experience deeper immersion and exploration during their psychedelic experience, improving antidepressant outcomes. In summary, exercise and psychedelics have numerous potential complementary mechanisms, therefore, future research is warranted to explore the efficacy, tolerability, safety, and neurobiology of this combination.
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Journal articleNutt D, 2026,
Medicines for Anxiety: A Hundred Years of Tranquillity and More to Come?
, Hum Psychopharmacol, Vol: 41 -
Journal articleLipson J, Kettner H, Carhart-Harris R, et al., 2026,
Baseline Mood and "Relational Triad" Predict Acute Qualities of Psychedelic Experience.
, Behav Sci (Basel), Vol: 16, ISSN: 2076-328XBACKGROUND: The quality and valence of psychedelic experiences are influenced by a range of psychological and contextual factors. This study examines baseline mood and the "relational triad"-comprising social connectedness, mindfulness, and spirituality-as potential predictors of the quality of naturalistic psychedelic experiences. METHODS: Data were drawn from the Predicting Responses to Psychedelics dataset, a longitudinal study tracking 654 individuals planning to take a psychedelic substance. Participants completed self-report measures at five time points, before and after ingestion. Baseline mood (depression, anxiety, and wellbeing) and relational triad factors were assessed at Timepoint 1, while acute psychedelic experience quality was measured at Timepoint 3 using validated scales (MEQ-30, CEQ, and ASC). RESULTS: Mystical and challenging experiences were weakly but positively correlated. Baseline depression and anxiety were predictive of more challenging experiences but not of mystical-type experiences, while baseline wellbeing predicted more mystical and less challenging experiences. Mindfulness and spirituality were positively associated with mystical experiences, while social connectedness and mindfulness were inversely associated with challenging experiences. CONCLUSIONS: These findings extend previous research by demonstrating that baseline psychological and relational factors shape the nature of psychedelic experiences.
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Journal articleKurtin DL, Herlinger K, Hayes A, et al., 2026,
Task-related differences in network connectivity and dynamics in people with severe opioid use disorder compared with healthy controls
, Translational Psychiatry, ISSN: 2158-3188One approach to addressing the immense unmet need for treatments of severe opioid use disorder (sOUD) is to understand more about associated changes in the brain’s reward circuitry. It has been shown that during reward anticipation in the Monetary Incentive Delay (MID) task, people with severe substance use disorder (SUD) show blunted responses in reward neural circuitry compared with healthy controls (HC). Conversely, drug-related cues result in heightened responses in the same neural reward circuitry in those with SUD compared with HC. However, it is unclear how such dysfunctional reward processing is related to neural correlates of other processes commonly dysregulated in addiction, such as attention and cognition. The aim of this work was to evaluate whether people with sOUD show different relationships between reward networks to networks that regulate cognition, attention, sensory processes, and more. Then, we evaluated whether there is a spatial relationship between differences in brain function and atlases of μ-opioid receptor (MOR) and dopamine D2 receptor (DRD2) availability. We collected fMRI data while people with sOUD receiving methadone (MD; n = 25) and HC (n = 22) completed the MID and cue reactivity tasks. We evaluated differences in functional connectivity (FC) and measures of brain state dynamics. Partial least squared (PLS) analysis computed the spatial relationship between FC metrics to MOR and D2DR availability. We found that MD participants generally exhibited weaker miFC compared to HC in both tasks except when comparing the difference in miFC during anticipation of monetary reward or drug related stimuli vs neutral stimuli. Contrasts between rewarding or drug-related to neutral stimuli showed MD participants had stronger miFC between reward/anti-reward networks to regions in the control network and default mode Network (DMN) in both tasks. Analysis of brain state dynamics showed the DMN was more prevalent i
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