INTRODUCTION:While some studies have linked early adversity to obsessive-compulsive disorder (OCD), not all findings are consistent, and the nature of these associations remains unclear. In particular, it is uncertain whether childhood trauma is more strongly related to features specific to OCD (e.g. onset age, severity, symptom dimensions) or to broader, clinical characteristics commonly observed in OCD but also in other psychiatric conditions (e.g., anxiety and depressive symptoms). The Global OCD study provided an opportunity to investigate these associations in a large multinational investigation of adult OCD. METHODS:A total of 268 individuals with OCD and 256 age- and sex-matched healthy controls (HCs) completed the Childhood Trauma Questionnaire (CTQ). CTQ total scores were compared between groups. Within the OCD group, regression models were used to examine associations between CTQ scores (total and subscale totals) and OCD-specific features (e.g., OCD onset age, OCD severity, obsessive-compulsive symptom dimensions) controlling for site, sex, age, socio-economic status (SES), and severity of anxiety and depression symptoms. Exploratory analyses further examined the association of CTQ with impulsivity/compulsivity scores, level of insight, and also severity of anxiety and depression symptoms controlling for covariates. All outcomes were fit as continuous (linear model), except OCD onset age, which was analyzed as a binary variable (<18 vs. ≥18 years). Statistical significance was set at p < 0.05 with correction for multiple comparisons in the exploratory analyses. RESULTS:Individuals with OCD, regardless of study site or sex, reported significantly higher levels of childhood trauma than HCs. Within the OCD group, no significant associations were found between overall childhood trauma severity (CTQ total score) and OCD-specific features (OCD onset age, OCD severity, and obsessive-compulsive symptom dimensions). Notably, greater severity of physical trauma (abuse and neglect) in childhood was significantly associated with more severe harm-related obsessive-compulsive symptoms. Exploratory analyses found greater childhood trauma (CTQ total and subscale scores) was significantly associated with impulsivity/compulsivity, level of insight, and severity of anxiety and depression symptoms. CONCLUSION:Childhood adversity appears to be more closely associated with broader clinical characteristics commonly detected in psychiatry rather than to features specific to OCD. These findings support prior research indicating that early trauma contributes broadly to psychiatric vulnerability rather than specifically to OCD. Nevertheless, the association of childhood physical trauma with harm-related obsessive-compulsive symptoms suggests the potential relevance of distinct forms of early adversity for particular OCD presentations. Further research is needed to clarify the mechanisms that underlie these associations, and their implications for treatment.

STUDY OBJECTIVES:Rates of cannabis use disorder (CUD) appear to be increasing nationally, with increases greater in states that legalized cannabis use. However, as legalization has progressed and stigma declined, some of these apparent increases could be due to greater willingness of survey respondents and patients to acknowledge cannabis involvement. Biological indicators of cannabis use overcome some concerns about trends denoted by self-report data whose validity is potentially changing over time. Our objective was to investigate the relationship between medical cannabis laws (MCL) and recreational cannabis laws (RCL) and the prevalence of cannabis-positive urine drug screens (UDS) in a large patient sample. METHODS:Veterans Health Administration (VHA) emergency department (ED) patients aged 18-75 years with ≥1 ED visit for any reason in a given year from 2008 to 2019 were included. Staggered-adoption difference-in-difference analysis was used to estimate the association between MCL and RCL enactment on cannabis-positive UDS, fitting adjusted linear binomial regression models. RESULTS:Adjusted cannabis-positive UDS prevalences increased from 16.4 % to 25.6 % in states with no cannabis law, 16.6 % to 27.6 % in MCL-only-enacting states, and 18.2 % to 33.8 % in RCL-enacting states. MCL-only and RCL enactment was associated with a 0.8 % (95 % CI, 0.4-1.0) and 2.9 % (95 % CI, 2.5-3.3) increase in prevalence of cannabis-positive UDS, respectively. CONCLUSIONS:MCL and RCL enactment played a significant role in the overall increases in cannabis-positive UDS among ED patients. The increase in a biological measure of cannabis use helps reduce concerns about reporting bias as cannabis becomes increasingly legalized.

Background: Aerobic exercise (AE) training has been shown to enhance aerobic fitness in people with schizophrenia. Traditionally, such training has been administered in person at gyms or other communal exercise spaces. However, following the advent of the COVID-19 pandemic, many clinics transitioned their services to telehealth-based delivery. Yet, at present, there is scarce information about the feasibility, safety, and efficacy of telehealth-based AE in this population. Objective: To examine the feasibility, safety, and efficacy of trainer-led, at-home, telehealth-based AE in individuals with schizophrenia. Methods: We analyzed data from the AE arm (n=37) of a single-blind, randomized clinical trial examining the impact of a 12-week AE intervention in people with schizophrenia. Following the onset of the COVID-19 pandemic, the AE trial intervention transitioned from in-person to at-home, telehealth-based delivery of AE, with the training frequency and duration remaining identical. We compared the feasibility, safety, and efficacy of the delivery of trainer-led AE training among participants undergoing in-person (pre-COVID-19; n=23) versus at-home telehealth AE (post-COVID-19; n=14). Results: The telehealth and in-person participants attended a similar number of exercise sessions across the 12-week interventions (26.8, SD 10.2 vs 26.1, SD 9.7, respectively; P=.84) and had similar number of weeks with at least 1 exercise session (10.4, SD 3.4 vs 10.6, SD 3.1, respectively; P=.79). The telehealth-based AE was associated with a significantly lower drop-out rate (telehealth: 0/14, 0%; in-person: 7/23, 30.4%; P=.04). There were no significant group differences in total time spent exercising (telehealth: 1246, SD 686 min; in-person: 1494, SD 580 min; P=.28); however, over the 12-week intervention, the telehealth group had a significantly lower proportion of session-time exercising at or above target intensity (telehealth: 33.3%, SD 21.4%; in-person: 63.5%, SD 16.3%; P<.001). There were no AE-related serious adverse events associated with either AE delivery format. Similarly, there were no significant differences in the percentage of participants experiencing minor or moderate adverse events, such as muscle soreness, joint pain, blisters, or dyspnea (telehealth: 3/14, 21%; in-person: 5/19, 26%; P>.99) or in the percentage of weeks per participant with at least 1 exercise-related adverse event (telehealth: 31%, SD 33%; in-person: 40%, SD 33%; P=.44). There were no significant differences between the telehealth versus in-person groups regarding changes in aerobic fitness as indexed by maximum oxygen consumption (VO(2)max; P=.27). Conclusions: Our findings provide preliminary support for the delivery of telehealth-based AE for individuals with schizophrenia. Our results indicate that in-home telehealth-based AE is feasible and safe in this population, although when available, in-person AE appears preferable given the opportunity for social interactions and the higher intensity of exercises. We discuss the findings' clinical implications, specifically within the context of the COVID-19 pandemic, as well as review potential challenges for the implementation of telehealth-based AE among people with schizophrenia.

Importance In the context of the US opioid crisis, factors associated with the prevalence of opioid use disorder (OUD) must be identified to aid prevention and treatment. State medical cannabis laws (MCL) and recreational cannabis laws (RCL) are potential factors associated with OUD prevalence. Objective To examine changes in OUD prevalence associated with MCL and RCL enactment among veterans treated at the Veterans Health Administration (VHA) and whether associations differed by age or chronic pain. Design, Setting, and Participants Using VHA electronic health records from January 2005 to December 2022, adjusted yearly prevalences of OUD were calculated, controlling for sociodemographic characteristics, receipt of prescription opioids, other substance use disorders, and time-varying state covariates. Staggered-adoption difference-in-difference analyses were used for estimates and 95% CIs for the relationship between MCL and RCL enactment and OUD prevalence. The study included VHA patients aged 18 to 75 years. The data were analyzed in December 2023. Main Outcome and Measures International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM ) or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification ( ICD-10-CM ) OUD diagnoses. Results From 2005 to 2022, most patients were male (86.7.%-95.0%) and non-Hispanic White (70.3%-78.7%); the yearly mean age was 61.9 to 63.6 years (approximately 3.2 to 4.5 million patients per year). During the study period, OUD decreased from 1.12% to 1.06% in states without cannabis laws, increased from 1.13% to 1.19% in states that enacted MCL, and remained stable in states that also enacted RCL. OUD prevalence increased significantly by 0.06% (95% CI, 0.05%-0.06%) following MCL enactment and 0.07% (95% CI, 0.06%-0.08%) after RCL enactment. In patients aged 35 to 64 years and 65 to 75 years, MCL and RCL enactment was associated with increased OUD, with the greatest increase after RCL enactment among older adults (0.12%; 95% CI, 0.11%-0.13%). Patients with chronic pain had even larger increases in OUD following MCL (0.08%; 95% CI, 0.07%-0.09%) and RCL enactment (0.13%; 95% CI, 0.12%-0.15%). Consistent with overall findings, the largest increases in OUD occurred among patients with chronic pain aged 35 to 64 years following the enactment of MCL and RCL (0.09%; 95% CI, 0.07%-0.11%) and adults aged 65 to 75 years following RCL enactment (0.23%; 95% CI, 0.21%-0.25%). Conclusions and Relevance The results of this cohort study suggest that MCL and RCL enactment was associated with greater OUD prevalence in VHA patients over time, with the greatest increases among middle-aged and older patients and those with chronic pain. The findings did not support state cannabis legalization as a means of reducing the burden of OUD during the ongoing opioid epidemic.

Importance Adverse childhood experiences (ACEs), potentially traumatic experiences occurring before the age of 18 years, are associated with epigenetic aging later in life and may be transmitted across generations. Objective To test evidence of the transmission of biological embedding of life experience across generations by analyzing maternal ACEs and epigenetic clocks measured in mothers during pregnancy and in their children at birth. Design, Setting, and Participants For this cross-sectional study, data from the Accessible Resource for Integrated Epigenomic Studies (ARIES) substudy of the Avon Longitudinal Study of Parents and Children (ALSPAC) were analyzed. The ALSPAC study recruited 14 541 women who gave birth in the Avon Health District in the UK between April 1, 1991, and December 31, 1992. The ARIES substudy comprised 1018 mother-offspring dyads based on the availability of DNA samples profiled in 2014. Epigenetic age was estimated using DNA methylation-based epigenetic clocks (including Horvath, Hannum, GrimAge, PhenoAge, and DunedinPACE) in mothers during pregnancy and the Knight and Bohlin cord blood epigenetic clocks in newborns. Analyses were performed between October 1, 2022, and November 30, 2023. Exposures A composite measure of maternal ACEs was the primary exposure in both maternal and offspring models; as a secondary analysis, individual ACEs were measured separately. The Edinburgh Postnatal Depression Scale (EPDS) was used to investigate depression during pregnancy as an exposure. Main Outcomes and MeasuresChanges in epigenetic age acceleration (EAA) were investigated as the primary outcome in maternal models during pregnancy. Changes in epigenetic gestational age acceleration (GAA) were the primary outcome in offspring analyses. Linear regression analyses were used to determine the association between maternal ACEs and both outcomes. Results This study included 883 mother-child dyads. The mean (SD) maternal age at delivery was 29.8 (4.3) years. Pregnant women with higher ACE scores exhibited higher GrimAge EAA (beta, 0.22 [95% CI, 0.12 to 0.33] years; P < .001). Maternal ACEs were not associated with GAA in newborns using P < .05 as a cutoff to determine statistical significance. Depression was associated with higher GrimAge EAA (beta, 0.06 [95% CI, 0.02 to 0.10] years; P = .01) in mothers during pregnancy, but not in newborns, and did not mediate the association between ACEs and EAA. Conclusions and Relevance The findings of this study suggest that maternal ACEs may be associated with epigenetic aging later in life, including during pregnancy, supporting a role for maternal ACEs in offspring development and health later in life.

A growing body of literature suggests that power spectral density (PSD) slope, measured using electroencephalography (EEG), might reflect synaptic activity and be a useful marker of early brain development. The objective of this article is to identify differences between preterm and full-term infants in PSD slope in active and quiet sleep. This is a secondary analysis of two studies, including premature (N = 33) (30 0/7 and 36 0/7 weeks' gestation) and full-term infants (N = 22). EEG was performed at near term-equivalent age in premature infants and within 36 h after birth in full-term infants. The natural log of the EEG power spectrum was plotted versus the natural log of the frequency spectrum. To estimate PSD slope, the power law exponent derived from the slope of the log(power) versus log(frequency) was calculated for the 1-20 Hz range and the 21-40 Hz range. Linear regression models were fit for each region in active and quiet sleep to examine the association between the PSD slope and infant age group. Preterm versus full-term infants demonstrated a less negative slope across multiple brain regions in active and quiet sleep. PSD slope may be an early measure of altered brain development in premature infants.

Dietary flavanols are food constituents found in certain fruits and vegetables that have been linked to cognitive aging. Previous studies suggested that consumption of dietary flavanols might specifically be associated with the hippocampal-dependent memory component of cognitive aging and that memory benefits of a flavanol intervention might depend on habitual diet quality. Here, we tested these hypotheses in the context of a large-scale study of 3,562 older adults, who were randomly assigned to a 3-y intervention of cocoa extract (500 mg of cocoa flavanols per day) or a placebo [(COcoa Supplement and Multivitamin Outcomes Study) COSMOS-Web, NCT04582617]. Using the alternative Healthy Eating Index in all participants and a urine-based biomarker of flavanol intake in a subset of participants [n = 1,361], we show that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. While the prespecified primary end point testing for an intervention-related improvement in memory in all participants after 1 y was not statistically significant, the flavanol intervention restored memory among participants in lower tertiles of habitual diet quality or habitual flavanol consumption. Increases in the flavanol biomarker over the course of the trial were associated with improving memory. Collectively, our results allow dietary flavanols to be considered in the context of a depletion-repletion paradigm and suggest that low flavanol consumption can act as a driver of the hippocampal-dependent component of cognitive aging.

Background and objective Estimating the contribution of risk factors of mortality due to COVID-19 is particularly important in settings with low vaccination coverage and limited public health and clinical resources. Very few studies of risk factors of COVID-19 mortality used high-quality data at an individual level from low- and middle-income countries (LMICs). We examined the contribution of demographic, socioeconomic and clinical risk factors of COVID-19 mortality in Bangladesh, a lower middle-income country in South Asia. Methods We used data from 290,488 lab-confirmed COVID-19 patients who participated in a telehealth service in Bangladesh between May 2020 and June 2021, linked with COVID-19 death data from a national database to study the risk factors associated with mortality. Multivariable logistic regression models were used to estimate the association between risk factors and mortality. We used classification and regression trees to identify the risk factors that are the most important for clinical decision-making. Findings This study is one of the largest prospective cohort studies of COVID-19 mortality in a LMIC, covering 36% of all lab-confirmed COVID-19 cases in the country during the study period. We found that being male, being very young or elderly, having low socioeconomic status, chronic kidney and liver disease, and being infected during the latter pandemic period were significantly associated with a higher risk of mortality from COVID-19. Males had 1.15 times higher odds (95% Confidence Interval, CI: 1.09, 1.22) of death compared to females. Compared to the reference age group (20–24 years olds), the odds ratio of mortality increased monotonically with age, ranging from an odds ratio of 1.35 (95% CI: 1.05, 1.73) for ages 30–34 to an odds ratio of 21.6 (95% CI: 17.08, 27.38) for ages 75–79 year group. For children 0–4 years old the odds of mortality were 3.93 (95% CI: 2.74, 5.64) times higher than 20–24 years olds. Other significant predictors were severe symptoms of COVID-19 such as breathing difficulty, fever, and diarrhea. Patients who were assessed by a physician as having a severe episode of COVID-19 based on the telehealth interview had 12.43 (95% CI: 11.04, 13.99) times higher odds of mortality compared to those assessed to have a mild episode. The finding that the telehealth doctors’ assessment of disease severity was highly predictive of subsequent COVID-19 mortality, underscores the feasibility and value of the telehealth services. Conclusions Our findings confirm the universality of certain COVID-19 risk factors—such as gender and age—while highlighting other risk factors that appear to be more (or less) relevant in the context of Bangladesh. These findings on the demographic, socioeconomic, and clinical risk factors for COVID-19 mortality can help guide public health and clinical decision-making. Harnessing the benefits of the telehealth system and optimizing care for those most at risk of mortality, particularly in the context of a LMIC, are the key takeaways from this study.

Objective: Cross-national work on neurocognitive testing has been characterized by inconsistent findings, suggesting the need for improved harmonization. Here, we describe a prospective harmonization approach in an ongoing global collaborative study. Method: Visuospatial N-Back, Tower of London (ToL), Stop Signal task (SST), Risk Aversion (RA), and Intertemporal Choice (ITC) tasks were administered to 221 individuals from Brazil, India, the Netherlands, South Africa, and the USA. Prospective harmonization methods were employed to ensure procedural similarity of task implementation and processing of derived task measures across sites. Generalized linear models tested for between-site differences controlling for sex, age, education, and socioeconomic status (SES). Associations with these covariates were also examined and tested for differences by site with site-by-covariate interactions. Results: The Netherlands site performed more accurately on N-Back and ToL than the other sites, except for the USA site on the N-Back. The Netherlands and the USA sites performed faster than the other three sites during the go events in the SST. Finally, the Netherlands site also exhibited a higher tolerance for delay discounting than other sites on the ITC, and the India site showed more risk aversion than other sites on the RA task. However, effect size differences across sites on the five tasks were generally small (i.e., partial eta-squared < 0.05) after dropping the Netherlands (on ToL, N-Back, ITC, and SST tasks) and India (on the RA task). Across tasks, regardless of site, the N-Back (sex, age, education, and SES), ToL (sex, age, and SES), SST (age), and ITC (SES) showed associations with covariates. Conclusions: Four out of the five sites showed only small between-site differences for each task. Nevertheless, despite our extensive prospective harmonization steps, task score performance deviated from the other sites in the Netherlands site (on four tasks) and the India site (on one task). Because the procedural methods were standardized across sites, and our analyses were adjusted for covariates, the differences found in cognitive performance may indicate selection sampling bias due to unmeasured confounders. Future studies should follow similar cross-site prospective harmonization procedures when assessing neurocognition and consider measuring other possible confounding variables for additional statistical control.

Background: In 2021, while overdose (OD) deaths were at the highest in recorded history, it is estimated that >80% of ODs do not result in a fatality. While several case studies have indicated that opioid-related ODs can result in cognitive impairment, the possible association has not yet been systematically investigated. Methods: 78 participants with a history of OUD who reported experiencing an OD in the past year (n=35) or denied a lifetime history of OD (n=43) completed this study. Participants completed cognitive assessments including the Test of Premorbid Functioning (TOPF) and the NIH Toolbox Cognition Battery (NIHTB-CB). Comparisons were made between those who experienced an opioid-related OD in the past year versus those who denied a lifetime OD history while controlling for factors including age, premorbid functioning, and number of prior ODs. Results: When comparing those who experienced an opioid-related OD within the past year to those without a history of OD, uncorrected standard scores were generally comparable; however, differences emerged in the multivariable model. Specifically, compared to those without a history of OD, those who experienced a past year OD evidenced significantly lower total cognition composite scores (coef. =-7.112; P=0.004), lower crystalized cognition composite scores (coef. =-4.194; P=0.009), and lower fluid cognition composite scores (coef. =-7.879; P=0.031). Conclusions: Findings revealed that opioid-related ODs may be associated with, or contribute to, reduced cognition. Extent of the impairment appears contingent upon individuals' premorbid intellectual functioning and the cumulative number of past ODs. While statistically significant, clinical significance may be limited given that performance differences (similar to 4 - 8 points) were not particularly robust. More rigorous investigation is warranted, and future studies must also account for the many other variables possibly contributing to cognitive impairment.

Importance:Cannabis use disorder (CUD) is increasing among US adults. Few national studies have addressed the role of medical cannabis laws (MCLs) and recreational cannabis laws (RCLs) in these increases, particularly in patient populations with high rates of CUD risk factors. Objective:To quantify the role of MCL and RCL enactment in the increases in diagnosed CUD prevalence among Veterans Health Administration (VHA) patients from 2005 to 2019. Design, Setting, and Participants:Staggered-adoption difference-in-difference analyses were used to estimate the role of MCL and RCL in the increases in prevalence of CUD diagnoses, fitting a linear binomial regression model with fixed effects for state, categorical year, time-varying cannabis law status, state-level sociodemographic covariates, and patient age group, sex, and race and ethnicity. Patients aged 18 to 75 years with 1 or more VHA primary care, emergency department, or mental health visit and no hospice/palliative care within a given calendar year were included. Time-varying yearly state control covariates were state/year rates from American Community Survey data: percentage male, Black, Hispanic, White, 18 years or older, unemployed, income below poverty threshold, and yearly median household income. Analysis took place between February to December 2022. Main Outcomes and Measures:As preplanned, International Classification of Diseases, Clinical Modification, ninth and tenth revisions, CUD diagnoses from electronic health records were analyzed. Results:The number of individuals analyzed ranged from 3 234 382 in 2005 to 4 579 994 in 2019. Patients were largely male (94.1% in 2005 and 89.0% in 2019) and White (75.0% in 2005 and 66.6% in 2019), with a mean (SD) age of 57.0 [14.4] years. From 2005 to 2019, adjusted CUD prevalences increased from 1.38% to 2.25% in states with no cannabis laws (no CLs), 1.38% to 2.54% in MCL-only enacting states, and 1.39% to 2.56% in RCL-enacting states. Difference-in-difference results indicated that MCL-only enactment was associated with a 0.05% (0.05-0.06) absolute increase in CUD prevalence, ie, that 4.7% of the total increase in CUD prevalence in MCL-only enacting states could be attributed to MCLs, while RCL enactment was associated with a 1.12% (95% CI, 0.10-0.13) absolute increase in CUD prevalence, ie, that 9.8% of the total increase in CUD prevalence in RCL-enacting states could be attributed to RCLs. The role of RCL in the increases in CUD prevalence was greatest in patients aged 65 to 75 years, with an absolute increase of 0.15% (95% CI, 0.13-0.17) in CUD prevalence associated with RCLs, ie, 18.6% of the total increase in CUD prevalence in that age group. Conclusions and Relevance:In this study of VHA patients, MCL and RCL enactment played a significant role in the overall increases in CUD prevalence, particularly in older patients. However, consistent with general population studies, effect sizes were relatively small, suggesting that cumulatively, laws affected cannabis attitudes diffusely across the country or that other factors played a larger role in the overall increases in adult CUD. Results underscore the need to screen for cannabis use and CUD and to treat CUD when it is present.

Background: The risk for cannabis use disorder (CUD) is elevated among U.S. adults with chronic pain, and CUD rates are disproportionately increasing in this group. Little is known about the role of medical cannabis laws (MCL) and recreational cannabis laws (RCL) in these increases. Among U.S. Veterans Health Administration (VHA) patients, we examined whether MCL and RCL effects on CUD prevalence differed between patients with and without chronic pain. Methods: Patients with [≥]1 primary care, emergency, or mental health visit to the VHA and no hospice/palliative care within a given calendar year, 2005-2019 (yearly n=3,234,382 to 4,579,994) were analyzed using VHA electronic health record (EHR) data. To estimate the role of MCL and RCL enactment in the increases in prevalence of diagnosed CUD and whether this differed between patients with and without chronic pain, staggered-adoption difference-in-difference analyses were used, fitting a linear binomial regression model with fixed effects for state, categorical year, time-varying cannabis law status, state-level sociodemographic covariates, a chronic pain indicator, and patient covariates (age group [18-34, 35-64; 65-75], sex, and race and ethnicity). Pain was categorized using an American Pain Society taxonomy of painful medical conditions. Outcomes: In patients with chronic pain, enacting MCL led to a 0.14% (95% CI=0.12%-0.15%) absolute increase in CUD prevalence, with 8.4% of the total increase in CUD prevalence in MCL-enacting states attributable to MCL. Enacting RCL led to a 0.19% (95%CI: 0.16%, 0.22%) absolute increase in CUD prevalence, with 11.5% of the total increase in CUD prevalence in RCL-enacting states attributable to RCL. In patients without chronic pain, enacting MCL and RCL led to smaller absolute increases in CUD prevalence (MCL: 0.037% [95%CI: 0.03, 0.05]; RCL: 0.042% [95%CI: 0.02, 0.06]), with 5.7% and 6.0% of the increases in CUD prevalence attributable to MCL and RCL. Overall, MCL and RCL effects were significantly greater in patients with than without chronic pain. By age, MCL and RCL effects were negligible in patients age 18-34 with and without pain. In patients age 35-64 with and without pain, MCL and RCL effects were significant (p<0.001) but small. In patients age 65-75 with pain, absolute increases were 0.10% in MCL-only states and 0.22% in MCL/RCL states, with 9.3% of the increase in CUD prevalence in MCL-only states attributable to MCL, and 19.4% of the increase in RCL states attributable to RCL. In patients age 35-64 and 65-75, MCL and RCL effects were significantly greater in patients with pain. Interpretation: In patients age 35-75, the role of MCL and RCL in the increasing prevalence of CUD was greater in patients with chronic pain than in those without chronic pain, with particularly pronounced effects in patients with chronic pain age 65-75. Although the VHA offers extensive behavioral and non-opioid pharmaceutical treatments for pain, cannabis may seem a more appealing option given media enthusiasm about cannabis, cannabis commercialization activities, and widespread public beliefs about cannabis efficacy. Cannabis does not have the risk/mortality profile of opioids, but CUD is a clinical condition with considerable impairment and comorbidity. Because cannabis legalization in the U.S. is likely to further increase, increasing CUD prevalence among patients with chronic pain following state legalization is a public health concern. The risk of chronic pain increases as individuals age, and the average age of VHA patients and the U.S. general population is increasing. Therefore, clinical monitoring of cannabis use and discussion of the risk of CUD among patients with chronic pain is warranted, especially among older patients.

Background Adverse childhood experiences (ACEs) are correlated with accelerated epigenetic aging, but it is not clear whether altered epigenetic aging from childhood adversities persists into adulthood and can be transmitted to the next generation. Thus, we tested whether mothers’ childhood adversity is associated with accelerated epigenetic aging during pregnancy and in their newborn offspring. Methods Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC) sub-study, Accessible Resource for Integrated Epigenomic Studies (ARIES). Women provided retrospective self-reports during pregnancy of ACE exposure. DNA methylation was measured in mothers during pregnancy and cord blood at birth. Estimates of epigenetic age acceleration were calculated using Principal Components of Horvath, Hannum skin & blood, GrimAge, PhenoAge, and DunedinPACE epigenetic clocks for mothers; and the Knight and Bohlin cord blood clocks for newborns. Associations between a cumulative maternal ACE score and epigenetic age acceleration were estimated using linear regression models, adjusting for maternal age at pregnancy, smoking during pregnancy, education, and pre-pregnancy BMI. Models for offspring were stratified by sex and additionally adjusted for gestation age. Results Mothers’ total ACE score was positively associated with accelerated maternal PhenoAge and GrimAge. In newborn offspring, mothers’ total ACE score was positively associated with accelerated epigenetic aging in males using the Bohlin clock, but not in females using either epigenetic clock. We found male offsprings’ epigenetic age was accelerated in those born to mothers exposed to neglect using the Knight clock; and parental substance abuse using the Bohlin clock. Conclusion Our results show that mothers’ ACE exposure is associated with DNAm age acceleration in male offspring, supporting the notion that DNAm age could be a marker of intergenerational biological embedding of mothers’ childhood adversity. This is consistent with findings on vulnerability of male fetuses to environmental insults.

Background Cannabis use disorder is associated with considerable comorbidity and impairment in functioning, and prevalence is increasing among adults with chronic pain. We aimed to assess the effect of introduction of medical cannabis laws (MCL) and recreational cannabis laws (RCL) on the increase in cannabis use disorder among patients in the US Veterans Health Administration (VHA). Methods Data from patients with one or more primary care, emergency, or mental health visit to the VHA in 2005-19 were analysed using 15 repeated cross-sectional VHA electronic health record datasets (ie, one dataset per year). Patients in hospice or palliative care were excluded. Patients were stratified as having chronic pain or not using an American Pain Society taxonomy of painful medical conditions. We used staggered -adoption difference -in -difference analyses to estimate the role of MCL and RCL enactment in the increases in prevalence of diagnosed cannabis use disorder and associations with presence of chronic pain, accounting for the year that state laws were enacted. We did this by fitting a linear binomial regression model stratified by pain, with time -varying cannabis law status, fixed effects for state, categorical year, time -varying state -level sociodemographic covariates, and patient covariates (age group [18-34 years, 35-64 years, and 65-75 years], sex, and race and ethnicity). Findings Between 2005 and 2019, 3 234 382-4 579 994 patients were included per year. Among patients without pain in 2005, 5 center dot 1% were female, mean age was 58 center dot 3 (SD 12 center dot 6) years, and 75 center dot 7%, 15 center dot 6%, and 3 center dot 6% were White, Black, and Hispanic or Latino, respectively. In 2019, 9 center dot 3% were female, mean age was 56 center dot 7 (SD 15 center dot 2) years, and 68 center dot 1%, 18 center dot 2%, and 6 center dot 5% were White, Black, and Hispanic or Latino, respectively. Among patients with pain in 2005, 7 center dot 1% were female, mean age was 57 center dot 2 (SD 11 center dot 4) years, and 74 center dot 0%, 17 center dot 8%, and 3 center dot 9% were White, Black, and Hispanic or Latino, respectively. In 2019, 12 center dot 4% were female, mean age was 57 center dot 2 (SD 13 center dot 8) years, and 65 center dot 3%, 21 center dot 9%, and 7 center dot 0% were White, Black, and Hispanic or Latino, respectively. Among patients with chronic pain, enacting MCL led to a 0 center dot 135% (95% CI 0 center dot 118-0 center dot 153) absolute increase in cannabis use disorder prevalence, with 8 center dot 4% of the total increase in MCLenacting states attributable to MCL. Enacting RCL led to a 0 center dot 188% (0 center dot 160-0 center dot 217) absolute increase in cannabis use disorder prevalence, with 11 center dot 5% of the total increase in RCL-enacting states attributable to RCL. In patients without chronic pain, enacting MCL and RCL led to smaller absolute increases in cannabis use disorder prevalence (MCL: 0 center dot 037% [0 center dot 027-0 center dot 048], 5 center dot 7% attributable to MCL; RCL: 0 center dot 042% [0 center dot 023-0 center dot 060], 6 center dot 0% attributable to RCL). Overall, associations of MCL and RCL with cannabis use disorder were greater in patients with chronic pain than in patients without chronic pain. Interpretation Increasing cannabis use disorder prevalence among patients with chronic pain following state legalisation is a public health concern, especially among older age groups. Given cannabis commercialisation and widespread public beliefs about its efficacy, clinical monitoring of cannabis use and discussion of the risk of cannabis use disorder among patients with chronic pain is warranted. Funding NIDA grant R01DA048860, New York State Psychiatric Institute, and the VA Centers of Excellence in Substance Addiction Treatment and Education. Copyright (c) 2023 Elsevier Ltd. All rights reserved.

BACKGROUND:Maintenance of cognitive abilities is of critical importance to older adults, yet few effective strategies to slow cognitive decline currently exist. Multivitamin supplementation is used to promote general health; it is unclear whether it favorably affects cognition in older age.OBJECTIVES:To examine the effect of daily multivitamin/multimineral supplementation on memory in older adults.METHODS:The COcoa Supplement and Multivitamin Outcomes Study Web (COSMOS-Web) ancillary study (NCT04582617) included 3562 older adults. Participants were randomly assigned to a daily multivitamin supplement (Centrum Silver) or placebo and evaluated annually with an Internet-based battery of neuropsychological tests for 3 y. The prespecified primary outcome measure was change in episodic memory, operationally defined as immediate recall performance on the ModRey test, after 1 y of intervention. Secondary outcome measures included changes in episodic memory over 3 y of follow-up and changes in performance on neuropsychological tasks of novel object recognition and executive function over 3 y.RESULTS:Compared with placebo, participants randomly assigned to multivitamin supplementation had significantly better ModRey immediate recall at 1 y, the primary endpoint (t(5889) = 2.25, P = 0.025), as well as across the 3 y of follow-up on average (t(5889) = 2.54, P = 0.011). Multivitamin supplementation had no significant effects on secondary outcomes. Based on cross-sectional analysis of the association between age and performance on the ModRey, we estimated that the effect of the multivitamin intervention improved memory performance above placebo by the equivalent of 3.1 y of age-related memory change.CONCLUSIONS:Daily multivitamin supplementation, compared with placebo, improves memory in older adults. Multivitamin supplementation holds promise as a safe and accessible approach to maintaining cognitive health in older age. This trial was registered at clinicaltrials.gov as NCT04582617.

Background: Opioid use disorder (OUD) continues to be major public health problem in the US and innovative medication strategies are needed. The extended-release injectable formulation of naltrexone (ER-NTX), an opioid receptor antagonist, is an effective treatment for OUD, but the need for an opioid-free period during the induction phase of treatment is a barrier to treatment success, particularly in the outpatient setting. Lofexidine, an alpha-2-adrenergic agonist, is an effective treatment for opioid withdrawal.Objectives: To evaluate the feasibility, safety, and tolerability of lofexidine for facilitating induction onto ER-NTX in the management of OUD.Methods: In an open-label, uncontrolled, 10-week outpatient clinical trial, 20 adults (four women) with OUD were treated with a fixed-flexible dosing strategy (maximum 0.54 mg 4x/daily) of lofexidine for up to 10 days to manage opioid withdrawal prior to receiving ER-NTX. The COVID-19 pandemic resulted in a modification of the study methods after enrolling 10 participants who attended all visits in person. The second group of 10 participants attended most induction period visits remotely.Results: Overall, 10 of the 20 participants (50%) achieved the primary outcome by receiving the first ER-NTX injection. Rates of induction success did not differ by the presence of fentanyl or remote visit attendance, although the small sample size provided limited statistical power. Six out of 20 participants (30%) initiated on lofexidine required dose adjustments. There were no study-related serious adverse events.Conclusions: This study provides preliminary evidence supporting the feasibility of inducting individuals with OUD onto ER-NTX using lofexidine.

Background Although cannabis legalization is associated with increases in self-report cannabis use, biological measures of cannabis use are needed to address potential bias introduced by improved self-reporting of cannabis use in states enacting medical cannabis laws (MCL) and recreational cannabis laws (RCL). Objective Quantify the role of MCL and RCL enactment in cannabis positive urine drug screen (UDS) prevalence among Veterans Health Administration (VHA) emergency department (ED) patients from 2008 to 2019. Design Staggered-adoption difference-in-difference analysis were used to estimate the role of MCL and RCL in cannabis positive UDS data, fitting adjusted linear binomial regression models to estimate the association between MCL and RCL enactment and prevalence of cannabis positive UDS. Participants VHA enrolled veterans aged 18-75 years with ≥1 ED visit in a given year from 2008 to 2019. Main Measures Receipt of ≥1 cannabis positive UDS during an ED visit were analyzed. Key Results From 2008 to 2019, adjusted cannabis positive UDS prevalences increased from 16.4% to 25.6% in states with no cannabis law, 16.6% to 27.6% in MCL-only enacting states, and 18.2% to 33.8% in RCL-enacting states. MCL-only and MCL/RCL enactment was associated with a 0.8% (95% CI, 0.4-1.0) and 2.9% (95% CI, 2.5-3.3) absolute increase in cannabis positive UDS, respectively. Significant effect sizes were found for MCL and RCL, such that 7.0% and 18.5% of the total increase in cannabis positive UDS prevalence in MCL-only and RCL states could be attributed to MCLs and RCLs. Conclusions In this study of VHA ED patients, MCL and RCL enactment played a significant role in the overall increases in cannabis positive UDS. The increase in a biological measure of cannabis use reduces concerns that previously documented increases in self-reported cannabis use from surveys are due to changes in patient willingness to report use as it becomes more legal. ### Competing Interest Statement Dr Hasin reported support from Syneos Health for an unrelated project. Dr Wall reported grants from the National Institute on Drug Abuse during the conduct of the study and grants from the National Institutes of Health outside the submitted work. Dr Saxon reported grants from the National Institute on Drug Abuse during the conduct of the study; consulting fees from Indivior, travel support from Alkermes, research support from MedicaSafe, and royalties from UpToDate outside the submitted work. No other disclosures were reported. ### Funding Statement Supported by the National Institute on Drug Abuse (grants R01DA048860 and K99DA055724), the New York State Psychiatric Institute, and the VA Centers of Excellence in Substance Addiction Treatment and Education. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by Institutional Review Boards at New York State Psychiatric Institute, VHA Puget Sound and VHA New York Harbor Healthcare Systems. 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 The data are not available.