Drug and Alcohol Dependence

Quantifying decision-making in experimental settings that mimic real-world conditions may provide insights into mechanisms underlying addiction. This study developed a computational model of opioid-seeking behavior. Out-of-treatment persons who regularly used heroin were stabilized on buprenorphine 8mg/day to minimize opioid withdrawal. Across programmatically-linked studies, three experimental conditions presented differing money vs. opioid unit amounts that could be earned per trial ($2 vs. 1-mg hydromorphone, n=23; $2 vs. 2-mg hydromorphone, n=36; $4 vs. 2-mg hydromorphone, n=24), controlling other factors. Progressive ratio schedules on each choice option required increasing effort across trials to earn the same amount. Trial-level outcomes were decision latency and choice on each option, and session-level outcomes were drug-money latency and breakpoint difference scores. A Markov computational model was used to predict the probability of choosing the same option as the previous trial (vs. switching). Model inputs included effort discrepancy (between earning the same vs. other commodity on next choice) and logarithm of the ratio of decisional speed (current vs. previous choice). Participants who more rapidly chose hydromorphone vs. money made more consecutive drug choices and expended greater effort earning hydromorphone. First-trial hydromorphone choice predicted continued effortful opioid-seeking. Participants repeated choices on 80% of trials; the model accurately predicted stick vs. switch behavior on 93% of trials. Participants typically repeated choices when faced with lower effort discrepancies and higher hydromorphone dose (2-mg vs. 1-mg). In conclusion, a Markov computational model accurately predicted effortful behavior in a choice paradigm that mimics real-world decisions between opioid and nondrug reinforcers.

Objectives Outpatient buprenorphine-naltrexone (bup-nx) treatment reduces overdose risk, yet many patients still return to use or disengage from treatment. We sought to understand how patients and prescribers experience and manage relapse risk, monitoring, and treatment agency in routine bup-nx treatment to identify gaps in current practice. Methods We conducted a qualitative needs assessment using semi structured, critical incident interviews with patients receiving outpatient bup-nx and prescribers who manage bup-nx treatment. Interviews examined situations involving relapse risk and empowerment in treatment decisions. We structured data collection and analysis using the Theoretical Domains Framework and COM B model to characterize determinants. Transcripts were coded deductively and inductively until code level saturation was reached. Results Participants (9 patients, 8 prescribers) described nine treatment needs mapped to the Capability, Opportunity, and Motivation components of the COM B model. These themes highlighted how patient agency in bup-nx treatment was constrained by physiologic and emotional states, with withdrawal, craving, pain, and distress often overriding longer term goals. Relapse vulnerability was experienced as dynamic and intensifying between visits, while clinical detection remained anchored to visit bound assessments, urine drug testing, refill patterns, and crisis driven contact, creating blind spots. Structural friction (pharmacy rules, insurance disruptions, transportation and housing instability), stigma from family and recovery communities, and motivational processes tied to fluctuating readiness and trust in monitoring further shaped engagement, disclosure, and dosing decisions; the same monitoring tools could either support honest disclosure or provoke concealment when perceived as punitive. Conclusions Relapse risk and agency in bup-nx treatment are negotiated as dynamic processes within structurally constrained and trust sensitive systems. Addressing the identified capability, opportunity, and motivation gaps will require patient centered, trust preserving approaches to monitoring and shared decision making.

Background: The nicotine analog 6-methyl nicotine (6-MN) has appeared in commercial e-cigarette liquids, and other products, spurring interest in determining the extent to which it conveys similar effects to those of nicotine. Objective: To determine if 6-MN acts like nicotine to decrease body temperature, decrease nociception, suppress wheel activity and reinforce operant behavior when delivered by vapor inhalation using an Electronic Nicotine Delivery System (ENDS; "e-cigarette") approach in a rat model. Methods: Male and female (N=8 per sex) young adult Sprague-Dawley rats were evaluated for rectal temperature and nociceptive responses (warm water tail-withdrawal) to the inhalation of vapor from (-)-6-MN or (-)-nicotine in concentrations ranging from 5-30 mg/mL in the propylene glycol vehicle. Rats were then assessed for the reinforcing effects of nicotine and 6-MN using a vapor self-administration procedure and the rate suppressing effects of nicotine and 6-MN on wheel activity following injection. Results: Inhalation of nicotine or 6-MN for 30 minutes decreased the rectal temperature and increased tail-withdrawal latency of female and male rats in a concentration-dependent manner. The magnitude of the effects of 6-MN and nicotine were similar at similar vapor concentrations. Operant responding for 6-MN vapor was increased by pre-treatment with the antagonist mecamylamine. 6-MN was more potent than nicotine at suppressing wheel activity after injection. Conclusions: 6-MN induces effects very similar to those of nicotine, at a similar potency when inhaled and at a slightly increased potency when injected.

Background: Opioid use disorder (OUD) is associated with a wide range of cognitive, affective, and motivational impairments, suggesting a disruption of large-scale brain systems that support diverse domains of functioning. Resting-state brain network segregation quantifies the degree of functional specialization within brain networks, is age-related, has been linked to brain glucose metabolism, and has been shown to be reduced in substance use disorders. We examined brain network segregation in individuals with OUD and non-OUD controls and tested associations with the duration of opioid use. Methods: Resting-state functional MRI data were collected from 149 individuals with OUD and 126 non-OUD controls. Functional connectivity was computed between brain regions assigned to functionally specialized networks supporting higher-order "association" or "sensorimotor" processes. For each network, segregation was quantified as the extent to which within-network connectivity exceeded between-network connectivity. Results: Individuals with OUD demonstrated lower segregation of the association and sensorimotor networks than non-OUD controls. Within the OUD group, more years of opioid use was associated with lower segregation of the association network, but not the sensorimotor network. Conclusions: OUD is characterized by overall lower resting-state brain network segregation. More years of opioid exposure was associated with lower association-network segregation, consistent with there being cumulative effects of chronic opioid use on large-scale brain organization, though causation could not be examined in this cross-sectional dataset. These findings identify altered network segregation as a potential neurobiological marker of OUD and suggest that restoration of brain network specialization is a measurable target of OUD treatment and potentially recovery.

Aims: To evaluate whether Cue-Induced Retrieval and Reconsolidation with Episodic Future Thinking (CIREF), which combines personalized drug-cue retrieval with structured future-oriented processing, produces greater changes in craving and delay discounting than a recent-past episodic active control in individuals with opioid use disorder receiving methadone maintenance treatment. Design: Multicentre, two-arm, parallel-group randomized controlled pilot trial with per-protocol analyses. Setting: Two outpatient addiction treatment and rehabilitation centres in Tehran, Iran. Participants: Thirty participants with opioid use disorder receiving methadone maintenance treatment were randomized to CIREF or Episodic Recent Thinking (ERT; n = 15 per group). Twenty-eight completed the intervention and were included in the analyses (n = 14 per group). Intervention and comparator: Participants completed one screening, baseline, and personalized cue-development session followed by three 75-minute intervention sessions. CIREF combined personalized drug-cue retrieval with future-oriented simulation, prediction, intention, and planning. ERT was structurally matched but anchored episodic processing to the recent past. Measurements: Primary craving outcomes comprised the three Desire for Drug Questionnaire (DDQ) subscales assessing session-level phasic/current craving immediately before and after each intervention session and the four Obsessive-Compulsive Drug Use Scale (OCDUS) subscales assessing tonic craving before and after the intervention period. The secondary outcome was Monetary Choice Questionnaire (MCQ) log(k), with more negative values indicating less steep delay discounting. Findings: After Holm correction across the three DDQ subscales, Group x Occasion interactions indicated greater reductions with CIREF for Desire and Intention to Drug Use, FGG(1.23, 32.09) = 24.37, pHolm < .001, partial eta-squared = .484, and Negative Reinforcement, FGG(1.35, 35.23) = 17.67, pHolm < .001, partial eta-squared = .405, but not Drug Abuse Control (pHolm = .172). After Holm correction across the four OCDUS subscales, only Desire and Mental Preoccupation with Drugs showed a significant Group x Time interaction, F(1, 26) = 12.35, pHolm = .007, partial eta-squared = .322; the remaining subscales were not significant (adjusted ps >= .177). MCQ log(k) showed a Group x Time interaction, F(1, 26) = 7.18, p = .013, partial eta-squared = .217; mean log(k) changed from -1.22 (0.36) to -1.80 (0.55) in CIREF and from -1.39 (0.32) to -1.44 (0.44) in ERT. Conclusions: In this small pilot sample, the future-oriented retrieval-based intervention produced greater changes than the recent-past active control in two dimensions of session-level phasic craving, one dimension of tonic craving, and monetary delay discounting. The results are preliminary and do not establish memory reconsolidation or effects on relapse or longer-term clinical outcomes.

Objectives: Tobacco and cannabis co-use is common, and reductions in one substance may theoretically lead to compensatory increases in the other. This secondary analysis examined whether cannabis cue-induced dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation (DLPFC-rTMS) affects tobacco consumption among tobacco-using individuals with cannabis use disorder (CUD). Methods: Data were analyzed from a randomized, sham-controlled trial of DLPFC-rTMS for CUD. Participants were treatment-seeking adults with moderate or severe CUD who reported baseline tobacco use. Active or sham 10-Hz DLPFC-rTMS was delivered during cannabis cue exposure over 10 treatment visits. Linear mixed-effects models examined group differences in weekly percentage change from baseline in tobacco consumption over treatment and follow-up, adjusting for baseline tobacco consumption. Additional models examined whether changes in cannabis use were associated with changes in tobacco use. Results: Twenty participants were included, with 10 assigned to active rTMS and 10 to sham. Active rTMS was associated with a greater reduction in tobacco consumption than sham at 1-week post-treatment (t = -2.49, p = 0.015). Changes in cannabis use were not significantly associated with group differences in tobacco reduction. Estimated group differences did not indicate compensatory increases in tobacco use among participants with larger reductions in cannabis use. Conclusions: Cannabis cue-induced DLPFC-rTMS was associated with a short-term reduction in tobacco consumption relative to sham among tobacco-using individuals with CUD. These preliminary findings suggest possible cross-substance effects of DLPFC-rTMS and did not indicate compensatory tobacco increases. Larger trials specifically designed for cannabis-tobacco co-use are warranted.

Background: Loneliness and social isolation may contribute to tobacco and nicotine use, but existing studies have been inconsistent. This systematic review and meta-analysis examined these associations among adults amid the evolving nicotine product landscape. Methods: A systematic search of PubMed, MEDLINE, PsycINFO, and CINAHL identified peer-reviewed quantitative studies published between 2014 and 2025 searched in February-April 2026. Eligible studies included adults aged [&ge;]18 years examining loneliness and/or social isolation in relation to smoking or nicotine use. Two reviewers independently screened studies, extracted data, and assessed risk of bias (using the National Heart, Lung, and Blood Institute risk of bias tool). Random effects meta-analyses were conducted to estimate pooled odds ratio (OR) with 95% confidence intervals (CIs). Results: 22 studies involving 273,954 participants met inclusion criteria, and 14 studies were included in the meta-analysis. A majority of the studies had low risk of bias. Meta-analysis findings showed that social isolation or loneliness was associated with significantly higher odds of nicotine product use (OR 1.84, 95% CI 1.48-2.29). Although no statistically significant association of nicotine product use and social isolation or loneliness (OR 1.35, 95% CI 0.72-2.53), some studies suggested bidirectional relationships, with smoking contributing to reduced social support and greater isolation over time. Sensitivity analysis showed the robustness of the meta-analysis findings. Subgroup analysis found no statistically significant differences were seen between subgroups defined by type of nicotine product, age groups, social isolation vs loneliness, measures of nicotine use behaviours and pre- vs post- COVID-19 pandemic period in the meta-regression. Limitations of included studies and analysis are discussed. Conclusions: Loneliness and social isolation are significant psychosocial correlates of nicotine product use. Cessation interventions may benefit from integrating social support and mental health strategies alongside traditional nicotine dependence treatment.

Introduction: Risk of recurrent opioid use during buprenorphine-naloxone (bup-nx) treatment is dynamic and remains elevated after initiation, with vulnerability shaped in part by treatment intensity and gaps between visits, yet routine outpatient care relies on episodic encounters and retrospective data. This mismatch can delay recognition of emerging instability and limit timely treatment adjustments. This paper reports the development and specification of an intervention strategy to address this mismatch. Methods: We used a structured, multi-phase design process to specify and configure a measurement-based care (MBC) strategy for bup-nx treatment (Bup-MBC) in outpatient addiction clinics through three phases: (1) a systematic review of patient-reported outcome measures (PROMs) for substance use treatment; (2) a qualitative needs assessment using the Theoretical Domains Framework and COM-B (Capability, Opportunity, Motivation-Behavior) model to identify gaps in risk monitoring, agency, and trust; and (3) iterative co-design with multidisciplinary clinicians to refine workflow fit and trust-preserving use of data. Patients informed item and feedback content during the needs assessment but did not participate in the co-design cycles. Results: Bup-MBC integrates (1) brief between-visit PROMs (e.g., withdrawal, craving, adherence); (2) immediate non-punitive patient feedback; (3) clinician-facing summaries and non-directive prompts in the electronic health record (EHR); and (4) an opt-in between-visit outreach pathway with predefined safety triggers, all configured within existing EHR and patient portal infrastructure. It targets patient and clinician capability to recognize changes in risk, opportunity for action through structured monitoring and visit preparation, and trust and agency through non-punitive communication, without adding substantial burden. The full measure set, severity bands, and question-to-action map are provided as supplementary material. Key trade-offs included prioritizing single-item measures for feasibility, balancing opt-in outreach with safety overrides, and assuming routine clinician use of summaries. Conclusion: This development study specifies an EHR-integrated MBC strategy for outpatient bup-nx treatment. As single-center design work with co-design limited to clinicians and delivery contingent on portal or text-message access, its outputs are hypotheses about mechanism and fit rather than demonstrated effects. Feasibility studies are needed to evaluate uptake, acceptability, workflow fit, and effects on treatment.

Background Alcohol-associated injury is a leading cause of emergency department (ED) utilization in the United States and a clinically important driver of preventable morbidity across the adult lifespan. Prior surveillance research has characterized how the rate and severity of alcohol-associated injury vary by patient age, but whether the seasonal timing of injury risk is equally predictable across age groups (a question directly relevant to the timing of clinical screening intensification and public health intervention) has not been formally tested. Methods We conducted a retrospective surveillance analysis of 45,876 alcohol-associated ED visits among adults aged 18 years and older, identified from the National Electronic Injury Surveillance System (NEISS), 2019-2025 (weighted national estimate: 2,092,319 visits), using the structured Alcohol_Involved indicator introduced into NEISS case abstraction in 2019. Patients were stratified by sex and five age groups (18-24, 25-34, 35-49, 50-64, and [&ge;]65 years). Single-harmonic cosinor (Poisson) regression was used to estimate the seasonal peak day of injury risk (acrophase) for each stratum. To assess reliability, we performed leave-one-year-out jackknife resampling (seven iterations per group), case-resampling bootstrap confidence intervals (1,000 iterations), and likelihood-ratio tests of seasonal-phase interactions. Results Peak injury timing differed significantly across age groups (X^2 [8] = 2356.2, p < .0001). Adults aged 25-64 years showed a highly reproducible early-to-mid-July peak, with jackknife estimates shifting [&le;]14 days when any single study year was excluded. Adults aged [&ge;]65 years showed significant seasonal variation annually (all p < .0001, amplitude comparable to younger groups) but a pooled peak estimate that shifted by up to 100 days across jackknife iterations. Sex-stratified analyses revealed that this instability was driven entirely by females aged [&ge;]65 years (jackknife range: 332 days, peak consistently in late October through early January) rather than males aged [&ge;]65 (jackknife range: 31 days, peak consistently in early August). Hospital admission rates increased monotonically with age from 9.0% (18-24 years) to 31.8% ([&ge;]65 years). Conclusions Alcohol-associated injury follows a reproducible, calendar-stable summer seasonal pattern in adults aged 25-64 years. Among adults [&ge;]65 years, the previously reported temporal instability is concentrated in the female subgroup, whose seasonal injury risk does not converge on a fixed calendar window. These findings suggest that fixed-calendar prevention and screening strategies are well suited to working-age adults and older men, but older women may require a year-round, individually tailored approach. Keywords: Alcohol-related injury; Emergency department; Seasonality; Age factors; Sex differences; Injury surveillance; Cosinor analysis; Older adults

Background: Substance use disorders (SUDs) remain common worldwide and inadequately treated. Neuromodulation targets neural circuits involved in reward, craving, and cognitive control. However, the primary research literature has not been systematically mapped regarding the relative contributions of clinical and preclinical studies. Methods: We conducted a multi-database bibliometric analysis of primary studies on neuromodulation for SUD. Web of Science, Scopus, and PubMed were searched covering 2000-2025. After scope classification and exclusion of secondary literature, 810 primary research documents remained. Performance analysis and science mapping were performed with bibliometrix and VOSviewer. Results: Scientific output grew at a compound annual growth rate of 14.16% (2001-2025), accelerating after 2015. Of 810 studies, 82.8% were clinical, 12.5% preclinical, and 4.7% mixed/translational. Alcohol (31.5%) and nicotine/tobacco (25.7%) dominated the literature and were overwhelmingly clinical (>92%), whereas cocaine and opioids retained larger preclinical shares (24-27%). Repetitive transcranial magnetic stimulation (rTMS) was the leading modality (31.6%), followed by deep brain stimulation (24.9%) and transcranial direct current stimulation (24.2%). Keyword co-occurrence revealed three clusters: a clinical neuromodulation core, a nicotine/tobacco axis, and a preclinical reward-circuitry module. The United States and China led in output. Conclusions: Neuromodulation research for SUD is expanding rapidly and is heavily skewed toward clinical investigations. A persistent clinical-preclinical asymmetry and limited explicitly translational work constitute structural features of the field. Greater integration between mechanistic and clinical research is needed to advance definitive trials.

Adolescent substance use is a major public health concern due to increased risk of future physical and mental health conditions. Fronto-striatal functioning - particularly regarding inhibition and reward processing - may increase vulnerability to high-risk substance use. However, it remains unclear if these neurobiological differences precede substance use or are consequences of it. The ongoing Adolescent Brain Cognitive Development (ABCD) Study follows over 10000 youth, offering an unprecedented opportunity to longitudinally examine substance use patterns throughout development. We utilized family-clustered time-varying Cox proportional hazard models to prospectively examine main and interaction effects of right Inferior Frontal Gyrus (IFG) inhibitory control and bilateral nucleus accumbens (NAc) reward response, alongside early life adversity and peer substance use as predictors of alcohol and cannabis onset in the ABCD Study. We identified a significant crossover interaction such that left NAc activity had a slight positive association with first full alcoholic drink in the context of higher right IFG activity but a negative association in the context of lower right IFG activity. However, peer alcohol and cannabis use emerged as the strongest predictors of outcomes. Alcohol onset was also more common in females, and early life adversity was associated only with cannabis onset. Findings indicate that interactions between inhibition- and reward-related brain regions may impact risk for early substance use onset, but these effects may be modest relative to socioenvironmental factors. Additionally, divergent alcohol and cannabis findings suggest that risk profiles are substance specific. Peer-focused strategies should be considered in preventive efforts.

Background: People with disabilities (PWD) represent over one-quarter of the US population and disproportionately experience chronic pain, yet limited research explores disparities they face in opioid use disorder (OUD) treatment. Objective: To examine disparities across disability status regarding opioid use disorder (OUD)-related outcomes and understand how chronic pain interacts with these associations. Methods: We completed a cross-sectional, secondary analysis of data from the All of Us Research Program, including 370,722 adults with electronic health record data available between January 2021-September 2023. We identified prevalence of disability, chronic pain, OUD, receipt of medications for OUD (MOUD), and OUD remission using diagnostic codes. We performed interaction analyses between chronic pain, disability subtype, and MOUD receipt in affecting OUD outcomes. Results: OUD was more common among individuals with physical (aOR: 2.74, 95% CI: 2.54-2.95), cognitive (2.19, 1.94-2.45), and multiple disabilities (2.43, 2.19-2.68), compared to those without disabilities. Among patients with OUD, those with physical disabilities were less likely to receive MOUD (0.81, 0.69-0.94). Compared to those without disabilities, chronic pain was associated with higher probabilities of OUD diagnosis and lower probabilities of MOUD and OUD remission across all subjects. These relationships were stronger for OUD diagnosis in cognitive disabilities, MOUD in multiple disabilities, and OUD remission in physical disabilities. Conclusions: Disability and chronic pain jointly shape disparities in OUD treatment and underscore the urgent need for care models that integrate OUD treatment with pain management and address the unique access challenges faced by people with disabilities.

Introduction: Self-rated health is an important patient-centred measure of health. The relationship between cannabis use and self-rated health has been previously studied, although with methodologic concerns which we aimed to address in this investigation. Methods: Propensity score weighted analyses of the National Health and Nutrition Examination Survey (NHANES) 2009-2018 were conducted. The primary exposure was self-reported cannabis use in the 30 days prior to survey response. The primary outcome was self-rated health measured on a five-level ordinal scale. Secondary outcomes included the number of days in the past months with: i) poor physical health, ii) poor mental health, and iii) activity limitations related to poor health. A weighted proportional odds regression model was used for the primary analysis and weighted zero-inflated negative binomial regression models were used for each secondary analysis. Results: Among 22,055 adults aged 20-59 responding to the NHANES cannabis questionnaire, 14.4% endorsed use in the past 30 days. After reweighting the sample to balance cannabis users and non-users across sociodemographic, medical, and lifestyle characteristics, there was no statistically significant association between recent cannabis use and higher levels of self-rated health (OR 0.90, 95% CI 0.80-1.01). Cannabis use was associated with poor mental health and activity limitations in the past month, but not poor physical health. Conclusions: Recent cannabis use was not associated with self-rated health but was associated with poor mental health and activity limitations in the past month. Cannabis users at risk of poor mental health should be connected with clinicians to help guide therapy.

Adults aged [&ge;]65 years are increasingly using cannabis products. However, controlled pharmacokinetic and pharmacodynamic data on {Delta}9-tetrahydrocannabinol (THC) in this population are sparse, and remain limited to oral/oromucosal formulations. To characterize the acute pharmacokinetic and pharmacodynamic effects of oral and vaporized THC in healthy adults aged [&ge;]65, we conducted a two-arm, randomized, double-blind, placebo-controlled trial in which 20 participants (mean age 70.0, SD: 5.1 years) received oral (placebo, 5 mg, or 10 mg) or vaporized THC (placebo, 2 mg, or 4 mg) across three eight-hour sessions separated by [&ge;]72 hours. Outcomes included plasma pharmacokinetics, subjective drug effects, reinforcement value, cognitive performance, heart rate (HR), blood pressure (BP), and adverse events (AEs). Oral THC was associated with delayed, lower THC exposure (Tmax 60-90 min; Cmax 2.6-6.2 ng/mL), with 11-OH-THC concentrations approximately matching parent-THC; slow-rising subjective effects; no change in reinforcement value; no significant change in HR or BP; and no AEs. Vaporized THC was associated with rapid, THC-dominant exposure (Tmax 3 min; Cmax 24.6-53.8 ng/mL) and minimal 11-OH-THC concentrations; rapid-onset subjective effects; increased reinforcement value at 4 mg; and significant HR elevation peaking within 5 min, without significant BP change. Cognitive performance did not differ from placebo at any oral or vaporized THC dose. At vaporized THC 4 mg, two participants experienced five AEs. Oral and vaporized THC produce route-specific pharmacokinetic and pharmacodynamic profiles in adults aged [&ge;]65, including an increase in reinforcement value only after vaporization, and should therefore not be treated as interchangeable in risk assessment for older adults.

Food addiction (FA) has been proposed as a phenotype sharing features with substance use disorders. Despite increasing recognition of food addiction as a behavioral phenotype with features overlapping substance use disorders, little is known about its prevalence or clinical significance among individuals with alcohol use disorder (AUD). Objective: To examine the prevalence of FA and to evaluate demographic, psychological, and alcohol-related correlates in individuals with AUD. Design, Setting, and Participants: This cross-sectional analysis included 743 adults with AUD who were either treatment seeking (Tx) (n = 534) for AUD and were enrolled in an inpatient program at the National Institutes of Health Clinical Center or not treatment-seeking (non Tx) (n = 209). Main Outcomes and Measures: FA symptoms were assessed using the Yale Food Addiction Scale, with >=2 symptoms categorized as FA in this report. Multivariable logistic regression models adjusted for age, education, and income were conducted separately within each cohort. Results: Among 743 adults with AUD, 238 (32.1%) met criteria for FA symptoms, with similar prevalence among Tx (32.6%) and nonTx (30.6%) participants despite marked differences in clinical characteristics. Across both cohorts, FA was independently associated with higher body mass index, greater psychological distress, and greater alcohol dependence severity. Childhood trauma and poorer sleep quality were additionally associated with FA among treatment-seeking participants, whereas alcohol-related measures differed according to treatment status. Conclusions and Relevance: FA was common among adults with AUD and was associated with greater psychological, behavioral, and metabolic burden regardless of treatment-seeking status. These findings suggest that FA identifies a clinically meaningful subgroup of individuals with AUD who may benefit from more comprehensive assessment and integrated treatment approaches.

Addiction is a complex and heritable trait which progresses through several developmental stages, each of which is presumably influenced by multiple partially overlapping genetic factors. Cocaine initially produces rewarding effects, followed by aversive effects including anxiety, craving, anhedonia, and withdrawal. These aversive effects have been suggested to contribute to the etiology of cocaine use disorders (CUD), as repeated exposure is thought to desensitize the rewarding effects and sensitize the aversive effects through a process involving both aberrant reward-based learning and aberrant avoidance-based learning. We examined the genetic basis of aversion learning using both food-based and cocaine-based behavioral assays in outbred Heterogenous Stock (HS) rats. A total of 1,074 HS rats (35.3% male) underwent runway operant cocaine-seeking, food-based progressive ratio and punishment testing, and locomotion testing. These phenotypes were significantly heritable (with h2 estimates as high as 0.307) and identified significant (p < 0.05) genetic loci related to avoidance-based learning including from the punishment task on Chromosomes 2, 3, 5, and 6, and the cocaine-operant runway latency task on Chromosome X. 172 positional candidate genes were identified from significant and suggestive loci, including Cdh10, Cdh12, Cdh18 which have previously been associated with smoking initiation from human GWAS, Adcy3, Cfap206, and Drc1 which are associated with primary neuronal cilia, as well as SNPs associated with novelty-related and social interaction phenotypes in independent samples of HS rats. Our results suggest that these aversion learning phenotypes are themselves complex heritable traits influenced by multiple genetic loci, which may pleiotropically affect other aspects of addiction biology.

Importance: Adolescent cannabis use is a growing concern due to its associations with long-term adverse mental health outcomes. However, the distinct, temporal associations of neurodevelopmental factors and childhood adverse life experiences (ALEs) with adolescent substance use in have not yet been fully elucidated. The Adolescent Brain Cognitive Development (ABCD) Study offers an unprecedented opportunity to prospectively examine neurobiological and socioenvironmental predictors of cannabis onset. Objective: To investigate magnetic resonance imaging-derived neurodevelopmental cortical brain Age Gap Estimate (brainAGE) and adverse life events as risk factors of early cannabis initiation. Design, Setting, and Participants: The ABCD Study is a longitudinal study across 22 sites in the United States. Data are collected starting at approximately 10 years old (currently at year-7 follow-up). Our analyses comprised 6688 (48% female) youth after exclusions. Main Outcomes and Measures: Cox proportional hazard models were computed to investigate brainAGE-sex interactions and 10 adversity dimensions at baseline as predictors of time to cannabis initiation up to age 18. Results: Mean age of initiation was 14.8 years (SD=1.43). Global brainAGE was modestly associated with cannabis initiation in females only (Hazard Ratio [HR]=1.05; 95% Confidence Interval [CI]=1.00-1.10, p = .049). Low socioeconomic status, caregiver substance use, family anger and arguments, and caregiver lack of supervision were associated with initiation (HRs = 1.11, 1.56, 1.09, 0.85, respectively; CIs = 1.04-1.19, 1.44-1.69, 1.09-1.19, 0.76-0.91, respectively; p's < .05). Other ALE dimensions and network-specific brainAGEs were not significantly associated with initiation. Conclusions and Relevance: Findings suggest that while cortical brainAGE may be somewhat increase vulnerability to adolescent cannabis use in females, its contributions are modest at best. In contrast, early childhood adversities such as socioeconomic factors and familial characteristics may present more substantive targets for prevention and intervention.

A body of research suggests that autistic individuals are less likely to drink alcohol than neurotypicals. However, emerging studies support a link between autism and alcohol use. This complex relationship is also reflected in studies that have examined the genetic overlap between the two traits. However, it is unclear whether there is a direct causal relationship between them. To explore this, we applied a combination of polygenic score and Mendelian randomisation analyses using publicly available genome-wide summary statistics and phenotypic measures of autism and alcohol consumption from UK Biobank. LD score regression analyses did not provide evidence of a genetic correlation between genetic liability for autism and drinks consumed per week (rg=-0.08; CI95%=-0.19, 0.03). Further, findings from polygenic score analyses did not support an association between genetic liability for autism and overall monthly alcohol intake. Univariable Mendelian randomisation analyses showed little evidence for a total effect of autism, attention deficit hyperactivity disorder (ADHD) or depression on overall monthly alcohol consumption. Multivariable Mendelian randomisation analyses also showed little evidence of a direct effect of autism on drinks per week when controlling for ADHD and depression. It is plausible that genetic liability for autism does not directly increase the amount of alcohol consumed but instead operates via commonly co-occurring difficulties in the autistic community. However, our findings may be due to methodological shortcomings, including weak instruments biasing effects towards to the null. Consequently, results should be interpreted with caution and further research conducted to address these issues.

In February 2021, Oregon became the first US state to decriminalize possession of small amounts of all commonly used illicit drugs (Measure 110); twenty-four days later, Washington's Supreme Court Blake ruling produced a weaker, shorter-lived decriminalization. Evaluations of these policy periods have focused on overdose deaths, with contested results; their association with the mental health of the general population is unknown. Using surveillance data on 6.3 million adult interviews (2011-2024) and synthetic control methods with permutation inference, we find frequent mental distress an estimated 2.15 percentage points higher in Oregon than in its synthetic counterfactual (largest positive gap among 45 jurisdictions; two-sided rank 2/45, p = 0.044, though not significant under the alternative fit-normalized statistic), with directionally consistent estimates in Washington and a joint test on the pair at p = 0.015. The increase concentrates in self-reported distress, among women and young adults, and is not mirrored in diagnoses, police-recorded partner violence or suicide.

Oregon (OR) and Colorado (CO) were the first states to enact regulations for provision of psilocybin with support of licensed "facilitators." As more states and countries adopt similar policies, informed public policy decisions require that client characteristics and rationale for using psilocybin, psilocybin dosing practices, mental health outcomes, and adverse events are understood. We performed a retrospective observational study of responses for 2363 individuals receiving psilocybin at OR and CO regulated service centers. Clients and facilitators entered data before and after receiving psilocybin, including the Mystical Experience Questionnaire-30 (MEQ-30), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and World Health Organization Well-Being Index-5 (WHO-5). Preexisting mental health issues were common (66%) in participants. Psilocybin doses ranged from 1-95 mg, with a mean total of 28*8 mg. We observed improvements of 49% in PHQ-9 scores, 51% in GAD-7 scores, and 22% in WHO-5 scores at two-weeks after dosing. MEQ-30 scores were dose-dependent. Changes in PHQ-9 and GAD-7 scores were not different for psilocybin doses [&le;]30 mg and >30 mg, and only weakly correlated with MEQ-30 scores. There were 94 mild adverse events during and after dosing, five more serious events not clearly related to treatment, and evidence of possible risk of increased suicidality. Study limitations include open label administration, self-reporting, loss of participants for follow-up, and a short 2-week post-dosing end-point. We conclude that psilocybin services, delivered within these regulated frameworks, is associated with improvements in mental health in real world populations, however, more robust monitoring is needed to ensure safety.