Youth alcohol use is a significant global health concern. Despite the widespread nature of alcohol use-related problems, the longitudinal effects of alcohol on brain structure in youth remain unclear. This review aimed to systematically synthesise the findings from the longitudinal structural magnetic resonance imaging (sMRI) literature on how alcohol use is associated with changes in brain structure in youth. Following PRISMA guidelines, five databases were searched, and studies of youth alcohol use that measured brain structure using sMRI at more than one time-point were included. A label-based meta-analysis (i.e., ratio of number of significant effects for a specific brain region to total number of analyses for that brain region) approach was employed to synthesise the findings. Sixteen studies were included. There was preliminary evidence that youth alcohol use is associated with reduced cortical volume (particularly in temporal regions) and attenuated increases in white matter volume over time. The role of pre-existing structural differences, and other moderating factors remains unclear due to limited research. Future longitudinal studies are needed to clarify the clinical significance of neurodevelopmental changes associated with youth alcohol use. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement DR and EM were supported by an Australian Government Research Training Program Scholarship. VL is supported by an AI and Val Rosenstrauss Senior Research Fellowship (2022 to 2026) and by a National Health and Medical Research (NHMRC) Investigator Grant (2023 to 2027 ID:2016833). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript

Background: State dissociation is commonly assessed using the Clinician Administered Dissociative States Scale (CADSS; 19-items). A briefer CADSS would have many advantages, enabling assessment of transient dissociative states and allowing repeated assessment within short intervals while minimizing participant burden. This is especially relevant in studies of dissociative drugs which cause sedation and psychomotor slowing. Here we describe the process of developing a short-form version of the CADSS (CADSS-SF), based on nitrous oxide (N2O) - induced dissociative responses in healthy volunteers.Methods: In the 'development phase', using data from three experimental pharmacological studies on N2O in healthy volunteers (n = 229), we identified the most 'N2O-responsive' items with the highest item-total correlations, endorsed by experts and consistent with published accounts on the phenomenology of drug-induced dissociation. Identified items were subjected to confirmatory factor analysis using a separate validation dataset (n = 80), which tested a series of one- and two-factor models with 6-8 items.Results: A 6-item, single-factor CADSS-SF consisted of derealization and depersonalization items and showed excellent model fit (χ2(9) = 0.246, p = .246, CFI/TLI>0.99, RMSEA = 0.059). The CADSS-SF was internally consistent (w = 0.87), correlated strongly with the full scale (r ≥ 0.88) and moderately with a measure of the related, but distinct construct of psychotomimesis (r = 0.63).Discussion: The CADSS-SF is a promising tool for rapid assessment of dissociation. It may be useful for capturing fleeting experimentally-induced dissociative phenomena that would otherwise be disrupted through the process of extended self-reporting, or for studying dissociation during drug intoxication, which is often accompanied by psychomotor slowing, sedation and inattention. The scale's brevity may allow tracking of changes in dissociation over relatively brief periods. However, like the parent long-form (19-item) CADSS, the CADSS-SF primarily captures variations in derealization/depersonalization only and may therefore be less appropriate for capturing the multidimensionality of dissociative phenomena. Further validation is required to establish the generalisability of the CADSS-SF beyond experimentally-(drug-) induced dissociation in healthy populations.

Setting up a psychedelic study can be a long, arduous, and Kafkaesque process. Researchers are faced with a host of challenges in this rapidly evolving field, necessitating a range of considerations that remain largely unstandardised. Many of the complexities inherent to psychedelic research also challenge existing assumptions around, for example, approaches to psychiatric prescribing, the conceptual framing of the placebo effect, and definitions of selfhood. This review paper aims to formalise these unique considerations by addressing the sociocultural, political, legal, pharmacological, safety, study design and experiential facets inherent to a psychedelic study. We bring together several of the major psychedelic research teams across the United Kingdom, identify continuing areas of debate, and provide a practical, comprehensive, experience-based guide, with recommendations for policymakers and future researchers intending to set up a psychedelic research study or clinical trial.

There is an ongoing need to identify novel pharmacological agents for the effective treatment of depression. One emerging candidate, which has demonstrated rapid-acting antidepressant effects in treatment-resistant groups, is nitrous oxide (N2O)—a gas commonly used for sedation and pain management in clinical settings and with a range of pharmacological effects, including antagonism of NMDA glutamate receptors. A growing body of evidence suggests that subanaesthetic doses of N2O (50%) can interfere with the reconsolidation of maladaptive memories in healthy participants and across a range of disorders. Negative biases in memory play a key role in the onset, maintenance, and recurrence of depressive episodes, and the disruption of affective memory reconsolidation is one plausible mechanism through which N2O exerts its therapeutic effects. Understanding N2O’s mechanisms of action may facilitate future treatment development in depression. In this narrative review, we introduce the evidence supporting an antidepressant profile of N2O and evaluate its clinical use compared to other treatments. With a focus on the specific memory processes that are thought to be disrupted in depression, we consider the effects of N2O on memory reconsolidation and propose a memory-based mechanism of N2O antidepressant action.

Background:Dissociative states, characterized by discontinuities in awareness and perception, occur in a diverse array of psychiatric disorders and contexts. These states have been experimentally modeled in the laboratory through various induction methods, but relatively little is known about the efficacy and comparability of different experimental methods. Methods:In this meta-analysis, we quantified dissociative states, as indexed by a standardized instrument (Clinician-Administered Dissociative States Scale), at baseline in varied diagnostic categories and in response to different experimental induction methods (psychological techniques and pharmacological agents) in both clinical and nonclinical samples. Primary outcomes were state dissociation effect sizes (Hedges' g) (PROSPERO registration: CRD42022384886). A total of 2214 articles were screened, which yielded 123 eligible articles and 155 effect sizes comprising 6692 individuals. Results:High levels of baseline state dissociation were observed in multiple diagnostic categories relative to controls, with the largest effects found in the dissociative and complex subtypes of posttraumatic stress disorder (PTSD-DC). In controlled experiments, induced state dissociation was most pronounced in response to mirror gazing and multiple pharmacological agents, with effects in ketamine and cannabis exceeding baseline state dissociation in PTSD-DC. The effect sizes were characterized by pronounced heterogeneity but were not reliably associated with methodological features of the original studies. Conclusions:Elevated state dissociation is present in multiple diagnostic categories, and comparable or higher levels can be reliably induced in controlled experiments using psychological techniques and pharmacological agents. These results demonstrate the efficacy of several methods for experimentally modeling dissociation and have implications for measuring adverse events and predicting outcomes in clinical interventions that involve pharmacological agents.

Direct and prolonged exposure to stress and uncertainty among healthcare workers (HCWs) during the COVID-19 pandemic likely had a significant negative impact on their mental health and general wellbeing. Although the contributors to such distress remain to be fully understood, the construct of perceived coercion appears to be relevant. Among HCWs, perceived coercion is conceptualised as appraisals about lack of control/‘freedom to choose’ and pressure to perform patient-care duties in the context of unprecedented threat of contagion from patients. To improve our understanding of perceived coercion amongst HCWs, we developed a 10-item scale—the Pandemic-specific Perceived Coercion Scale for Healthcare Workers (PPCS-HCW) scale—designed to be adaptable and applicable for use in future mass-contagion emergencies. A preliminary (exploratory) factor analysis (N = 546) showed that relevant items coalesced around three factors—‘internal pressure’, ‘external pressure’ and ‘perceived coercion’, that partly overlap with previous conceptualisations of perceived coercion. The exploratory conceptual and psychometric structure was confirmed in a separate sample of HCWs from the UK and Norway (N = 483). On average, across the three PPCS-HCW scale factors, HCWs showed low levels of perceived coercion (M = 0.22 (95% CI [0.11, 0.33] on a − 3 to + 3 scale). However, cluster analysis identified three groups: low (− 1.09 (95% CI [− 1.20, − 0.99]), moderate (0.17 (95% CI [0.08, 0.25]) and high scoring (1.57 (95% CI [1.47, 1.67]) PPCS-HCW clusters. High scoring participants showed higher levels of psychological distress, avoidance coping and compassion fatigue. In summary, our findings suggest that perceived coercion is a relevant construct in understanding the adverse psychological impact of large-scale contagion emergencies on HCWs.

BACKGROUND:Physiological signals conveyed by the vagus nerve may generate quiescent psychological states conducive to contemplative practices. This suggests that vagal neurostimulation could interact with contemplative psychotherapies (e.g. mindfulness and compassion-based interventions) to augment their efficacy. METHODS:In a fully factorial experimental trial, healthy adults (n = 120) were randomized to transcutaneous vagus nerve stimulation (tVNS) plus Self-Compassion-Mental-Imagery Training (SC-MIT) or alternative factorial combinations of stimulation (tVNS or sham) plus mental imagery training (MIT: SC-MIT or Control-MIT). Primary outcomes were self-reported state self-compassion, self-criticism, and heart rate variability (HRV). Exploratory outcomes included state mindfulness and oculomotor attentional bias to compassion-expressing faces. Most outcomes were assessed acutely on session 1 at the pre-stimulation (T1), peri-stimulation (T2), and post-MIT + stimulation (T3) timepoints, and after daily stimulation+MIT sessions (eight sessions). RESULTS:During session 1, a significant Timepoint × Stimulation × MIT interaction (p = 0.025) was observed, reflecting a larger acute T1→T3 increase in state self-compassion after tVNS+SC-MIT, with similar rapid effects on state mindfulness. Additionally, significant Session × MIT and Session × Stimulation interactions (p ≤ 0.027) on state mindfulness (but not self-compassion) suggested that tVNS+SC-MIT's effects may accumulate across sessions for some outcomes. By contrast, changes in state self-criticism and compassion-related attentional bias were only moderated by MIT (not stimulation) condition. HRV was unaffected by stimulation or MIT condition. CONCLUSION:tVNS augmented the effects of SC-MIT and might, therefore, be a useful strategy for enhancing meditation-based psychotherapies. Our findings also highlight the value of oculomotor attentional metrics as responsive markers of self-compassion training and the continued need for sensitive indices of successful vagal stimulation.

Disturbed sleep is a key component of posttraumatic stress disorder (PTSD) symptomology, and sleep disturbances and PTSD have a bidirectional association. In the context of a larger experimental intervention study we evaluated the impact of pre-trauma sleep on intrusive memory frequency and characteristics, including distress, vividness, and avoidance, in healthy women after analogue trauma exposure. Using the trauma film paradigm as an experimental model of trauma exposure, healthy female participants (N = 120) reported baseline sleep characteristics using the Pittsburgh Sleep Quality Index and viewed a distressing film, then listened to either a 30-minute guided yoga nidra meditation or instrumental music. Intrusive memory frequency and characteristics (vividness, distress, avoidance and sense of ‘nowness’) were monitored in the acute period immediately after the film and over 1-week (‘long-term’). Worse sleep quality predicted greater acute memory avoidance and distress and greater acute and long-term vividness and nowness. Lower sleep duration was associated with greater avoidance of acute intrusions. Neither sleep quality nor duration was associated with intrusion frequency. Sleep over the month prior to an analogue trauma predicted intrusive memory characteristics acutely and long-term, though its impact varied depending on the specific sleep metric —quality versus duration. In contrast with previous analogue and naturalistic trauma studies, while baseline sleep predicted intrusive memory characteristics, it did not predict the frequency of intrusive memories. This research further underlines the impact of baseline sleep on the development of psychological symptoms after trauma exposure and suggests that trauma memory characteristics, in addition to frequency of intrusions, are a potentially informative outcome in trauma-sleep studies. These findings may have implications for development of preventative interventions aimed at reducing the subjective impact of intrusive memories after stressful events and improving key sleep metrics in the immediate aftermath of such events. This research was supported by a National Institute of Health predoctoral trainee stipend.

INTRODUCTION:Cannabis use disorder (CUD) affects ∼33 million people globally and can be underscored by intense cravings to use cannabis, which can trigger compulsive use and relapse. Functional MRI (fMRI) evidence demonstrates hyperactivity of addiction brain pathways during cannabis cue-reactivity, consistent with prominent neuroscientific theories of addiction, particularly within the anterior cingulate cortex (ACC). The ACC also emerges as a key region of real-time fMRI-based neurofeedback (fMRI-neurofeedback) studies demonstrating voluntary changes during cravings in persons who use substances. However, this notion is untested in CUD. METHODS AND ANALYSIS:We aim to develop a protocol that tests the feasibility of fMRI-neurofeedback to enable persons with a moderate-to-severe CUD to increase the activity of the ACC during cannabis-induced craving to provide mechanistic insights on treatment targets; and decrease ACC activity during cue-induced craving to pave the way for reducing brain reactivity. The primary outcome measure is the change in ACC activity during fMRI-neurofeedback compared with a non-regulation condition. ETHICS AND DISSEMINATION:This feasibility study has been approved by the Human Research Ethics Committee of Australian Catholic University. On completion, the findings from this study will be published in academic journals, presented at conferences and disseminated to clinicians and to individuals who use cannabis. The results from this feasibility study have the potential to inform the conduct of powered trials to examine how fMRI-neurofeedback can identify and reduce craving-related brain dysfunction in CUD.

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychedelic drug known for its uniquely profound effects on consciousness; however, it remains unknown how it affects the brain. We collected electroencephalography (EEG) data of 29 healthy individuals before and after inhaling a high dose (12-mg) of vaporized synthetic 5-MeO-DMT. We replicate results from rodents showing amplified low-frequency oscillations but extend these findings by characterizing the complex organization of spatiotemporal fields of neural activity. We find that 5-MeO-DMT radically reorganizes low-frequency flows, causing them to become heterogeneous, viscous, and nonrecurring and to cease their travel forward and backward across the cortex. Further, we find a consequence of this reorganization in broadband activity, which exhibits more stable low-dimensional behavior with increased energy barriers for rapid global shifts. These findings provide a detailed empirical account of how 5-MeO-DMT sculpts human brain dynamics, revealing a set of atypical cortical slow-wave behaviors with significant implications for neuroscientific models of serotonergic psychedelics.

The potential of meditation as a preparatory tool for psychedelic experiences lacks empirical investigation. We surveyed experienced practitioners (N=123) with substantial histories in both meditation and psychedelic use to examine meditation’s role in psychedelic preparation. Respondents expected meditation training to primarily enhance acceptance and present-moment focus during psychedelic experiences, while also increasing oceanic boundlessness and reducing anxious ego-dissolution. For practitioners with limited meditation experience (1-3 years) and fewer psychedelic sessions (1-20), those adhering to specific meditation traditions reported significantly higher PBMPP scores (Perceived Benefits of Meditation for Psychedelic Preparation) compared to non-adherents. However, among highly experienced meditators (10+ years) with limited psychedelic experience (1-20 sessions), this pattern reversed, with non-adherents reporting significantly higher PBMPP scores than adherents to specific tradition. When evaluating specific meditation approaches, Loving-Kindness Meditation emerged as the most beneficial preparatory practice, significantly outrating other approaches such as Focused Attention. Exploratory factor analysis of meditative elements identified three distinct components: Positive Emotional States (PES), Mindful Awareness and Insight (MAI), and Concentration Techniques (CT), with PES receiving the strongest endorsement for psychedelic preparation. For practical implementation, participants recommended approximately three weeks of preparation with 30-minute daily sessions, strongly favouring online and asynchronous delivery methods. These results provide empirical groundwork for developing effective evidence-based meditation protocols for psychedelic preparation. They also highlight the importance of considering psychedelic users’ level of previous meditation experience in optimising such interventions. Future research directions should include controlled trials examining specific meditation practices’ effects on psychedelic experiences and outcomes across different populations and contexts.

Background This study examined perceptions of coercion, pressures and procedural injustice and how such perceptions influenced psychological well-being in those who experienced a UK COVID-19 lockdown, with a view to preparing for the possibility of future lockdowns. Methods 40 individuals categorised as perceiving the lockdown(s) as either highly or lowly coercive took part in one of six asynchronous virtual focus groups (AVFGs). Results Using thematic analysis, the following key themes were identified in participants’ discussions: (1) Choice, control and freedom; (2) threats; (3) fairness; (4) circumstantial factors; and (5) psychological factors. Conclusions As the first qualitative study to investigate the psychological construct of perceived coercion in relation to COVID-19 lockdowns, its findings suggest that the extent to which individuals perceived pandemic-related lockdowns as coercive may have been linked to their acceptance of restrictions. Preparing for future pandemics should include consideration of perceptions of coercion and efforts to combat this, particularly in relation to differences in equity, in addition to clarity of public health messaging and public engagement.

Meditation can benefit well-being and mental health, but novices often struggle to effectively recognize and disengage from mental processes during meditation due to limited awareness, potentially diminishing meditation's benefits. We investigated whether personalised high-precision neurofeedback (NF) can improve disengagement from mental activity during meditation and enhance meditation's outcomes. In a single-blind, controlled, longitudinal paradigm, 40 novice meditators underwent two consecutive days of meditation training with intermittent visual feedback from either their own (N=20) or a matched participant's (N=20; control group) posterior cingulate cortex (PCC) activity measured using 7 Tesla functional magnetic resonance imaging. During training, the experimental group showed stronger functional decoupling of PCC from dorsolateral prefrontal cortex, indicating better control over disengagement from mental processes during meditation. This led to greater improvements in emotional well-being and mindful awareness of mental processes during a week of real-world self-guided meditation. We provide compelling evidence supporting the utility of high-precision NF-guided meditation training to optimise real-world meditation practice for well-being.

Psychedelic substances are garnering renewed interest for their potential therapeutic applications, yet the mechanisms by which challenging experiences during psychedelic use contribute to positive outcomes remains poorly understood. Here we present a mixed-methods investigation into the strategies individuals employ to navigate difficult psychedelic experiences and their relationship to emotional breakthrough. Qualitative analysis of accounts from psilocybin retreat participants (n = 16) informed the development of the Responses to Challenging Psychedelic Experiences Inventory (ReCiPE). In a subsequent online survey (n = 529), exploratory factor analysis of the ReCiPE revealed three primary response strategies: Acceptance and Reappraisal, Sensory Regulation and Physical Interaction, and Social Support and Disclosure. Exploratory correlation and multiple regression analyses demonstrated significant relationships between different types of challenges, response strategies and emotional breakthrough. Notably, Acceptance and Reappraisal, and Social Support and Disclosure strategies were positively associated with greater emotional breakthrough. Fear-related challenges were negatively associated with emotional breakthrough and involved fewer adaptive coping strategies. These findings elucidate the complex interplay between challenging experiences and adaptive responses in psychedelic contexts, offering insights for optimising therapeutic protocols and enhancing safety in both clinical and non-clinical settings.

Psychedelic substances induce profound alterations in consciousness. Careful preparation is therefore essential to limit adverse reactions, enhance therapeutic benefits, and maintain user safety. This paper describes the development of a self-directed, digital intervention for psychedelic preparation. Drawing on elements from the UK Medical Research Council (MRC) framework for developing complex interventions, the design was informed by a four-factor model of psychedelic preparedness, using a person-centred approach. Our mixed-methods investigation consisted of two studies. The first involved interviews with 19 participants who had previously attended a ‘high-dose’ psilocybin retreat, systematically exploring their preparation behaviours and perspectives on the proposed intervention. The second study engaged 28 attendees of an ongoing psilocybin retreat in co-design workshops, refining the intervention protocol using insights from the initial interviews. The outcome is a co-produced 21-day digital course (Digital Intervention for Psychedelic Preparation (DIPP)), that is organised into four modules: Knowledge-Expectation, Psychophysical-Readiness, Safety-Planning, and Intention-Preparation. Fundamental components of the course include daily meditation practice, supplementary exercises tied to the weekly modules, and mood tracking. DIPP provides a comprehensive and scalable solution to enhance psychedelic preparedness, aligning with the broader shift towards digital mental health interventions.

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychedelic drug known for its uniquely profound effects on subjective experience, reliably eradicating the perception of time, space, and the self. However, little is known about how this drug alters large-scale brain activity. We collected naturalistic electroencephalography (EEG) data of 29 healthy individuals before and after inhaling a high dose (12mg) of vaporised synthetic 5-MeO-DMT. We replicate work from rodents showing amplified low-frequency oscillations, but extend these findings with novel tools for characterising the organisation and dynamics of complex low-frequency spatiotemporal fields of neural activity. We find that 5-MeO-DMT radically reorganises low-frequency flows of neural activity, causing them to become incoherent, heterogeneous, viscous, fleeting, nonrecurring, and to cease their typical travelling forwards and backwards across the cortex compared to resting state. Further, we find a consequence of this reorganisation in broadband activity, which exhibits slower, more stable, low-dimensional behaviour, with increased energy barriers to rapid global shifts. These findings provide the first detailed empirical account of how 5-MeO-DMT sculpts human brain dynamics, revealing a novel set of cortical slow wave behaviours, with significant implications for extant neuroscientific models of serotonergic psychedelics. ### Competing Interest Statement The authors have declared no competing interest.

Preparing participants for psychedelic experiences is crucial for ensuring these experiences are safe, and potentially, beneficial. However, there is currently no validated measure to assess the extent to which participants are well-prepared for such experiences. Our study aimed to address this gap by developing, validating, and testing the Psychedelic Preparedness Scale (PPS). Using a novel iterative Delphi-focus group methodology (‘DelFo’) followed by qualitative pre-test interviews, we incorporated the perspectives of expert clinicians/researchers and of psychedelic users, to generate items for the scale. Psychometric validation of the PPS was carried out in two large online samples of psychedelic users (N = 516; N = 716), and the scale was also administered to a group of participants before and after a 5–7-day psilocybin retreat (N = 46). Exploratory and confirmatory factor analysis identified four factors from the 20-item PPS: Knowledge-Expectations, Intention-Preparation, Psychophysical-Readiness, and Support-Planning. The PPS demonstrated excellent reliability (ω = 0.954) and evidence supporting convergent, divergent and discriminant validity was also obtained. Significant differences between those scoring high and low (on psychedelic preparedness) before the psychedelic experience were found on measures of mental health/wellbeing outcomes assessed after the experience, suggesting that the scale has predictive utility. By prospectively measuring modifiable pre-treatment preparatory behaviours and attitudes using the PPS, it may be possible to determine whether a participant has generated the appropriate mental ‘set’ and is therefore likely to benefit from a psychedelic experience, or at least, less likely to be harmed.