INTRODUCTION:Bipolar II disorder (BD-II) is characterised by hypomanic and depressive episodes with the latter tending to dominate the clinical course of the disorder, and they are often associated with suicidality. Despite available guideline-based recommendations for first-line pharmacological treatments, patient outcomes remain suboptimal, especially for those with chronic depression and suicidal ideation. The dearth of viable treatment options for this population is evident, which is where psychedelics propose an additional alternative path. Psilocybin has recently shown promise in treating major depressive disorder and treatment-resistant depression; however, individuals with bipolar disorder or suicidality are typically excluded from such trials due to safety concerns (ie, risk of emerging suicidal behaviour, psychosis and/or mania). Here, we present the protocol of a study which aims to explore the acceptability, safety and treatment preferences of psilocybin-assisted therapy in patients with BD-II struggling with suicidal ideation. METHODS AND ANALYSIS:This outpatient, single-site, phase II, single-arm, open-label clinical trial feasibility study will include 10 participants diagnosed with BD-II depression and moderately passive suicidal ideation. Participants may receive up to two oral doses of 25 mg psilocybin, approximately 4 weeks apart, alongside a structured therapeutic protocol (based on mindfulness cognitive-behavioural therapy) that includes preparatory therapy sessions, psychological support during administration and post-treatment integration therapy sessions. The purpose is to examine the acceptability and safety of using psilocybin as a therapeutic for mild to moderate suicidality in patients currently diagnosed with BD-II and to obtain preliminary data on its effects. This will be measured using the following: Primary outcomes include change in suicidality, that is, the Interpersonal Needs Questionnaire and the Columbia Suicide Severity Rating Scale from baseline to main endpoint (3 weeks post initial administration) and feasibility and acceptability (as assessed by number of participants who complete the trial, number of therapy sessions attended and number of assessments completed). Secondary outcomes include changes in the following associated measures: Montgomery-Asberg Depression Rating Scale, Quick Inventory of Depressive Symptomatology, Young Mania Rating Scale, Brief Psychiatric Rating Scale Positive Symptom Subscale, Altman Self-Rating Mania Scale. Findings will also be used to estimate effect sizes and inform the design of a future randomised controlled trial. ETHICS AND DISSEMINATION:Ethical approval has been obtained from the UTHealth Committee for the Protection of Human Subjects (CPHS RB# HSC-MS-23-0905). The results of the study will be disseminated to the public (ie, clinicians, researchers, patients and policymakers) through peer-reviewed journals, conferences and scientific meetings and clinical registries. TRIAL REGISTRATION NUMBER:NCT06706232.

Alterations of GABAA receptors (GABAARs) following chronic alcohol are thought to be related to deficits in GABAergic signaling in individuals with alcohol use disorder (AUD). Whether those modifications affect the function of synaptic GABAARs is not clear, as the electrophysiological characterization of native synaptic receptors from AUD individuals had not been done. To obtain this information, we microtransplanted synaptic membranes from postmortem dorsolateral prefrontal cortex (DLPFC) samples of AUD and non-AUD subjects to determine functional traits of GABAARs. To follow the path from transcription to function of potential changes of GABAARs in AUD, GABAARs currents and GABA pEC50 values were integrated with RNA-Seq and label-free proteomics datasets of bulk tissue and isolated synaptosomes from the same subjects. Our results outline significant reconfigurations in transcriptomic organization of GABAARs in AUD, higher levels of GABRG1 and significant decrease of mitochondrial transcripts in AUD individuals. Notably, transcriptional differences were gradually lost as the analysis moved from transcription to protein and function within our cohort. This suggests post-translational buffering in AUD resulting in unchanged GABA receptor synaptic activity. Our novel findings establish a proof of concept for reactivating AUD post-synaptic receptors and integrating this information with multiple levels of multi-omic analyses, as well as outline hypothesis-generating insights into this multifaceted disease.

Aims. The current “fourth wave” of the U.S. opioid crisis is defined by increased polysubstance use, particularly fentanyl combined with stimulants, conferring greater risk of fatal overdose. This study characterized patterns of polysubstance use at time of death in a convenience sample of fatal overdose decedents. Methods. Cases were drawn from The University of Texas Health Science Center at Houston Brain Collection. Toxicology reports were obtained from the Harris County Institute of Forensic Sciences. Deaths occurred between 2016 and 2025. Metabolites were attributed to parent drugs as appropriate. Drugs were collapsed into 25 classes. Exploratory data analysis characterized the extent and heterogeneity of polysubstance use at time of death. The Gini-Simpson index quantified the diversity of the combinations (GSI = probability that two randomly selected decedents have different observed combinations). Results. Data from 73 overdose decedents were analyzed (mean age = 41.1 years; 72.6% male; 71.2% White, 19.2% Black, 8.2% Hispanic). Decedents had M = 3.5 parent drugs detected and M = 2.5 implicated as cause of death (COD), representing M = 2.8 drug classes detected and M = 2.2 implicated as COD. At least four drugs were detected in 43.8% of cases (26.0% for COD). Of 51 drug-class combinations in COD determinations, 86.3% were only observed in single cases (GSI = .96). Conclusions. Polysubstance use was pervasive, and specific combinations were heterogeneous. The simplifying assumptions required to make this complexity tractable for epidemiological or pharmacogenomic modeling may involve substantial tradeoffs between parsimony and granularity, even in much larger samples.

RATIONALE:Classical psychedelics-a broad class of compounds that include psilocybin, lysergic acid diethylamide, dimethyltryptamine, and mescaline-have shown significant promise for the treatment of mental health conditions in recent clinical trials. Organizations such as the National Network of Depression Centers (NNDCs) can play a pivotal role in uniting researchers and clinicians working in this field to explore and synthesize existing evidence as well as characterize emerging challenges. OBJECTIVES:We outline several categories of challenges that have emerged in the context of clinical trials with psychedelic drugs, drawing from our collective empirical observations as well as the extant literature. While these challenges have been presented in the context of clinical trial environments, many of them are likely to persist if and when psychedelic treatments become approved and are implemented in psychiatric clinical practice. RESULTS:We describe four categories of challenges in the context of clinical trial participants-(1) treatment nonresponse, (2) expectancy effects and functional unblinding, (3) post-session psychological difficulties, and (4) contagion effects-and provide management strategies for study teams to mitigate associated risks. CONCLUSIONS:Classical psychedelics show therapeutic promise as mental health treatments. Studying them properly presents unique and unprecedented challenges that require researchers to develop sophisticated strategies to navigate nonresponse, expectancy effects, functional unblinding, post-session psychological issues, and possible contagion effects to responsibly advance this field. The NNDC and similar organizations are well-positioned to guide best practices and ensure the responsible advancement of this promising field.

In recent years psychedelics have gained popularity and potential promise in the field of mental health, but for patients diagnosed with bipolar disorder (BD), fears of emerging manic or psychotic symptoms have caused investigators to exclude them from psychedelic research. In this observational study, we explore the motivations, expectations, and personality characteristics of individuals with BD who have either used (i.e., experimenters) a classic psychedelic (i.e., psilocybin, LSD) or were considering using (i.e., contemplators) in the near future. We compared so-called experimenters to contemplators across various sociodemographic, psychological, and mental health variables. The groups did not differ in socio-demographic variables or mental health, however, experimenters demonstrated more positive attitudes towards psychedelics and more 'openness to experience.' Furthermore, certain motives for use were more strongly endorsed while contemplators expressed concerns about potential negative effects and outcomes. These findings highlight that previous psychedelic experience is associated with more positive perceptions and motivations for use, which might have also been shaped by the actual experience. While we do not advocate for unsupervised use of psychedelics outside of a clinical setting, the study provides some information what areas need to be discussed with individuals with BD who contemplate using psychedelics, even in the context of a clinical trial.

Structural and functional alterations in the brain's reward circuitry are present in cocaine use disorder (CocUD), but their molecular underpinnings remain unclear. To investigate these mechanisms, we performed single-nuclei multiome profiling on postmortem caudate nucleus tissue from six individuals with CocUD and eight controls. We profiled 30,030 nuclei, identifying 13 cell types including D1- and D2-medium spiny neurons (MSNs) and glial cells. We observed 1485 differentially regulated genes and 10,342 differentially accessible peaks, with alterations in MSNs and astrocytes related to neurotransmitter activity and synapse organization. Gene regulatory network analysis identified transcription factors including ZEB1 as exhibiting distinct CocUD-specific subclusters, activating downstream expression of ion- and calcium-channels in MSNs. Further, PDE10A emerged as a potential drug target, showing conserved effects in a rat model. This study highlights cell type-specific molecular alterations in CocUD and provides targets for further investigation, demonstrating the value of multi-omics approaches in addiction research.

Psychological autopsies are a well-established tool for understanding contributing factors in suicide completion. These tools have been used less often to understand personality characteristics of people with other manners of death (e.g. overdose). This study examined personality characteristics related to the manner of death in 83 autopsy cases using the UTHealth Psychological Autopsy Interview Schedule (UTH-PAIS), a psychological autopsy which assesses the presence of mental illness or substance use disorder but also includes items to capture transdiagnostic personality factors. Exploratory factor analysis of the items assessing personality factors was used to examine patterns in personality, and these factors were confirmed via k-means clustering. This analysis uncovered four distinct personality factors: (1) perseverance and self-regulation, (2) aggression, (3) sensitivity to rejection, and (4) extraversion. Of these personality factors, only perseverance and self-regulation differed by the manner of death. Individuals who died of natural causes or by completed suicide had a higher perseverance and self-regulation factor score than those who died by substance overdose, and these patterns were further supported by cluster analysis. The findings suggest that, in this autopsy sample, suicide was a planned, rather than an impulsive, act, though this interpretation is made cautiously given the sample size which also prohibited analysis of overdose death between those with vs. without a prior suicide attempt. Additionally, the results support prior work suggesting substance use disorders are associated with poor self-regulation, which may contribute to overdose deaths in these individuals. The study demonstrates the utility of psychological autopsy for studying personality factors related to the manner of death in cases where ante mortem data is unavailable.

BACKGROUND:Learning Health Networks (LHNs), such as the one described in Savitz et al. (in press), involve employing a network of treatment centers to produce standardized data from routine clinical practice, produce knowledge from that data, and systematically use that knowledge to inform care. To date, there are limited examples of LHNs in psychiatry. It is essential to establish robust dialogue around best practices for building LHNs to advance precision medicine in psychiatry. METHODS:A task group consensus on key elements of LHNs as applied to mood disorders was convened. Task group members reviewed current literature and ongoing LHN network efforts and evaluated opportunities and gaps within psychiatry broadly, and mood disorders specifically. RESULTS:Task group members noted four key considerations for building LHNs for mood disorders. First, obtain qualitative and quantitative stakeholder input at every stage of development, specifically input from patients and patients' families, clinicians and health system leadership. Second, collect data on objective measures of functioning, such as neuropsychological testing, quality of life indicators, and blood-based markers of health, alongside more standard measures such as symptom severity. Third, carefully consider the details of how new evidence-based practices will be identified and implemented. Fourth, identify a plan for sustainability. LIMITATIONS:Literature was reviewed and discussed among expert task group members, but this was not a systematic review. CONCLUSIONS:With stakeholder input, data on functioning as well as symptom severity, thoughtful implementation strategies, and an eye to sustainability, LHNs represent an important opportunity for advancement in the treatment of mood disorders.

Purpose of Review This commentary summarizes how the intense and distinctive subjective effects of psychedelics complicate tests of the efficacy and mechanisms of action (MOAs) of psychedelic-assisted treatments (PATs) for mental-health conditions. Specifically, we discuss (a) how estimates of PAT efficacy are confounded under functional unblinding and (b) uncertainty surrounding whether subjective or neurobiological effects are causal therapeutic MOAs of PATs. We then review methodological solutions to address these challenges. Recent Findings Several novel methodologies have been discussed in the literature. For testing PAT efficacy under functional unblinding, potential solutions include improved active placebo conditions, expectancy-focused recruitment and consent procedures, better measurement of expectancies and blinding, and more rigorous statistical modeling. For testing whether subjective effects are causal MOAs in PATs, strategies that disentangle the subjective and neurobiological effects of psychedelics are needed. Potential methods include administering psychedelics under general anesthesia, developing non-psychoactive psychedelic analogues, leveraging Mendelian randomization, and studying psychedelic microdosing. Participant safety and ethical considerations are critical for many of these strategies. Ultimately, combining multiple innovative methods may offer the most robust insights. Summary Future empirical efforts to develop these strategies will be crucial for advancing our limited understanding of whether and how PATs achieve clinical benefits in psychiatry.

Substance use disorders (SUDs) contribute to early-onset age-related diseases and represent a major global health burden. Accelerated biological aging (AA) has been proposed as a key factor behind SUD-related morbidity and mortality. This study aimed to elucidate the molecular basis of AA in SUD by analyzing transcriptomic profiles in postmortem dorsolateral prefrontal cortex tissue from individuals with SUD, including alcohol (AUD), opioid (OUD), and stimulant use disorders (StUD). We examined brain tissue from 58 donors to assess differential aging patterns and AA across SUD using epigenetic clocks specifically designed for brain tissues (DNAmClock Cortical , CerebralCortexClock common , and PCBrainAge). Samples were then stratified into those with and without AA to perform differential expression analyses across groups and to identify biological pathways potentially related to AA. Analyses identified multiple differentially expressed genes linked to AA, revealing unique and overlapping biological pathways within SUD subtypes. Further, our analysis highlighted shared aging mechanisms across SUD subtypes, particularly mitochondrial signaling and metabolic processes. While insightful, these subtype-specific findings remain exploratory due to limited statistical power. Most biological pathways underlying AA in SUD appear to be subtype-specific, with distinct molecular signatures influenced by substance type. Given the cross-sectional design, causal interpretations are limited. Further research may support targeted interventions for aging-related risks in SUD populations.

Objective: 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 Mont-gomery-& Aring;sberg 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 cor-relation coefficient r = 0.508) and Visual Restructuralization (r = 0.516), and EBI (r = 0 & sdot;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

Psychedelic substances such as psilocybin have recently gained attention for their potential therapeutic benefits in treating depression and other mental health problems. However, individuals with bipolar disorder (BD) have been excluded from most clinical trials due to concerns about manic switches or psychosis. This study aimed to systematically examine the effects of recreational psychedelic use in individuals with BD. Using the Timeline Followback (TLFB) method, we assessed mood symptoms, substance use, and other mental health-related variables in the month before and three months following participants' most recent psychedelic experience. Results showed a significant reduction in depressive symptoms and cannabis use, an increase in the number of days without mental health symptoms, and an increase in the number of days with hallucinogen use. Importantly, no significant changes in (hypo)manic, psychotic, or anxiety symptoms were observed. These findings suggest that psychedelics may hold potential as a safe and effective treatment for BD, though further research, including randomized controlled trials, is needed.

Purpose: Self-management and lifestyle interventions are a key factor in treatment outcomes for persons with bipolar disorder (BD). A virtual environment (VE), due to it's ability to provide flexibility of involvement in its platform, may be an alternative to face-to-face treatment to provide support for self-management. The purpose of this study is to explore how a VE, developed for chronic illness self-management, may be modified to promote self-management and lifestyle changes in those with BD. Method: This study used a qualitative description design with focus groups. Data were collected via minimally structured interviews and analyzed using thematic content analysis. A total of seven focus groups were conducted, and the sample consisted of 30 adults with BD. Age range was 21-77 years with 21 females, seven males, and two non-binary individuals. Results: Five themes emerged from the findings: Self-management and lifestyle interventions with regards to (1) mental health; (2) holistic health; (3) role of peers; (4) involvement of the family; (5) technological aspects of the VE. Conclusions: Focus group participants suggested that the VE may be an efficacious way to enhance selfmanagement and promote lifestyle interventions in those with BD. Research is needed to adapt such platforms to the need of the patients and examine its' effect on health outcomes.

Background: Psilocybin and psychedelic-assisted therapy (PAT) have gained renewed interest due to recent findings that PAT can enhance therapeutic outcomes. In 2019, the U.S. Food & Drug Administration (FDA) approved breakthrough therapy status to psilocybin for the treatment of depression, but PAT has yet to be approved as a therapeutic treatment for mental health disorders. Should the FDA approve PAT, medical students will serve as gatekeepers to PAT. Methods: Medical students (n = 295) were surveyed and randomized to two terminology conditions (i.e., "psilocybin" or "magic mushrooms, MMs") assessing their attitudes, knowledge, and beliefs. Results: Regardless of the terminology utilized, medical students held overall positive attitudes but their attitudes were significantly more positive when the term "psilocybin" was used. Furthermore, experience with psychedelics was associated with significantly more positive attitudes, beliefs, and higher self-rated knowledge. Finally, attitudes and beliefs were significant predictors of medical students' willingness to recommend PAT, if FDA approved, after controlling for covariates (e.g., personal experience with psychedelics). Conclusions: Despite some limitations, based on this study, using the term "psilocybin" might be preferable over "MMs" in a research or educational context. Although personal experience positively affects opinions toward psychedelics, beliefs and attitudes seem to be more relevant when it comes to actual medical advice.

IntroductionTo understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function.MethodsBuilding on the growing appreciation that miRNAs can cross the blood-brain barrier, we carried out miRNA profiling in same-subject postmortem samples from BA9 and blood tissues.ResultsmiRNA–mRNA network analysis showed that even though miRNAs identified in BA9 and blood were fairly distinct, their target genes and corresponding enriched pathways overlapped strongly. Among the dominant enriched biological processes were tissue development and morphogenesis, and MAPK signaling pathways. These findings point to robust, redundant, and systemic opioid-induced miRNA dysregulation with a potential functional impact on transcriptomic changes. Further, using correlation network analysis, we identified cell-type specific miRNA targets, specifically in astrocytes, neurons, and endothelial cells, associated with OUD transcriptomic dysregulation. Finally, leveraging a collection of control brain transcriptomes from the Genotype-Tissue Expression (GTEx) project, we identified a correlation of OUD miRNA targets with TGF beta, hypoxia, angiogenesis, coagulation, immune system, and inflammatory pathways.DiscussionThese findings support previous reports of neurovascular and immune system alterations as a consequence of opioid abuse and shed new light on miRNA network regulators of cellular response to opioid drugs.