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Genetic variations in the human mu-opioid receptor gene (OPRM1) mediate individual differences in response to pain and opiate addiction. We studied whether the common A118G (rs1799971) mu-opioid receptor single nucleotide polymorphism (SNP) was associated with overdose severity in humans. In addition, we examined an SNP responsible for alternative splicing of OPRM1 (rs2075572). We assessed allele frequencies of the above SNPs and associations with clinical severity in patients presenting to the emergency department (ED) with acute drug overdose. This work was designed as an observational cohort study over a 12-month period at an urban teaching hospital. Participants consisted of consecutive adult ED patients with suspected acute drug overdose for whom discarded blood samples were available for analysis. Specimens were linked with clinical variables (demographics, urine toxicology screens, clinical outcomes) then deidentified prior to genetic SNP analysis. Blinded genotyping was performed after standard DNA purification and whole genome amplification. In-hospital severe outcomes were defined as either respiratory arrest (RA; defined by mechanical ventilation) or cardiac arrest (CA; defined by loss of pulse). We analyzed 179 patients (61% male, median age 32) who overall suffered 15 RAs and four CAs, of whom three died. The 118G allele conferred 5.3-fold increased odds of CA/RA (p

Objective: To investigate the association between prenatal cannabis use and perinatal outcomes using longitudinal data from pregnant individuals., Study Design: This secondary-data analysis study utilized data collected from 894 pregnant individuals followed in the Stress in Pregnancy longitudinal study, conducted between 2009 and 2013. The status of cannabis use was ascertained through interviews and electronic medical record reviews to evaluate the effect of cannabis use on perinatal outcomes (NICU admission, preterm delivery, low birth weight, fetal death)., Results: Among participants analyzed, 13.1% used cannabis, who were generally younger (25.9 vs 27.9 years). There was a sevenfold increased risk of fetal death (OR 7.30) among cannabis users relative to non-users. Elevated risk persisted after adjustments of potential confounders (aOR 6.31). Adjusted models also suggested increased low birth weight risk (aOR 1.67)., Conclusion: This study highlights an association between prenatal cannabis use and elevated risks for fetal death and low birth weight., (© 2024. The Author(s).)

Background: In this review, we provide an updated assessment of available evidence on the pharmacokinetics (PK) of CBD and explore the impact of different factors on PK outcomes. Materials and Methods: This systematic review and meta-regression analysis was preregistered (PROSPERO: CRD42021269857). We systematically searched Medline, Embase, PsycInfo, and Web of Science Core Collection up to November 19, 2022. Trials of CBD in healthy adults were included if they reported at least one of the PK parameters of interest, including T max , C max , AUC 0-t , AUC 0-inf , and T 1/2 , in serum or plasma. Studies of patient populations or CBD co-administration with other medications were excluded. The National Heart, Lung, and Blood Institute's Quality Assessment Tool for Before-After Studies with no Control Group was used. Random-effects multivariable meta-regression analysis was conducted. Results: A total of 112 trial arms from 39 studies were included; 26 trial arms had a "Good" quality, 70 "Fair," and 16 "Poor." Eight arms used inhalation CBD, 29 oromucosal, 73 oral, and 2 intravenous. CBD formulations could be categorized to nanotech ( n =14), oil-based ( n =21), alcohol-based ( n =10), water-based ( n =12), Sativex ( n =17), and Epidiolex ® ( n =22). For single-dose studies, CBD doses ranged between 2 and 100 mg in inhalation, 5-50 mg in oromucosal, and 0.42-6000 mg in oral administration. Sixty-six trial arms had only male participants or a higher number of male than female participants. The duration of the PK session was between 4 and 164 h. A higher CBD dose was associated with higher C max , AUC 0-t , and AUC 0-inf . Compared with oral administration, oromucosal administration was associated with lower C max , AUC 0-t , and AUC 0-inf . Fed status was associated with higher C max and AUC 0-t when compared with the fasting status. A higher ratio of female participants was associated with lower T max in oral administration and higher C max . Conclusion: As expected, CBD dose, route of administration, and diet were major determinants of CBD PK with oral routes providing higher bioavailability and nanotechnology formulations a faster onset. Although CBD appeared to have a faster onset and longer duration in women, more studies are required to delineate the role of biological sex. Factors that influence CBD PK have implications for medication development and appropriate dosing in clinical practice.

Background: Cannabidiol (CBD) is a widely available cannabis product with many claims as to potential health benefits including alleviating symptoms related to opioid use disorder (OUD). However, little is known as to how individuals with OUD perceive CBD, to what extent they may already be using CBD, and for what purposes., Methods: A survey was conducted among individuals receiving treatment for OUD at the Addiction Institute of Mount Sinai in New York City from July 2021 to August 2023. The survey consisted of demographic questions, questions about opioid use, CBD use, and perceptions regarding CBD. Statistical analysis using ordinal logistic regression was employed to compare perceptions between CBD users and non-users while adjusting for age and race., Results: Among 587 respondents, 550 completed the survey. Among all survey completers, 129 (23%) reported a history of using CBD for a variety of reasons including: anxiety (81, 62.8%), pain (65, 50.4%), sleep (63, 48.8%), depression (62, 48.1%), recreational purposes (32, 24.8%), or for other reasons (8, 6.2%). Of note, 22 (17.1%) respondents reported using CBD to control their addiction and 54 (41.9%) reported using CBD to ease opioid withdrawal symptoms. CBD users demonstrated more positive perceptions regarding its legality (β = 0.673, OR = 1.960, 95% CI [1.211, 3.176], p = .006), social acceptance (β = 0.718, OR = 2.051, 95% CI [1.257, 3.341], p = .004), and therapeutic potential compared to non-users. CBD users also had a more positive view of its potential future role in managing addiction (β = 0.613, OR = 1.846, 95% CI [1.181, 2.887], p = .007)., Conclusions: This study highlights a significant association between CBD usage and progressive views regarding CBD among individuals with OUD, suggesting a growing interest in CBD as a potential adjunctive therapy for individuals in substance use treatment. Some patients are already using CBD for anxiety, pain, sleep, depression, or as a harm reduction intervention to control their addiction or for opioid withdrawal symptoms. These findings underscore the importance of integrating patient perspectives into future research and treatment strategies involving CBD in the context of OUD., (© 2024. The Author(s).)

We appreciate the comments of Gilman et al. (2023) on our paper and their acknowledgement of its importance in highlighting the significance of this area of research. Further, their acknowledgment that the primary results of our study are in a range that is similar to those from other published studies of children exposed to highly stressful environmental events emphasizes the validity of our findings and the important extension of our results to children experiencing these events in utero. They, however, raised concerns about some of the results regarding specific types of psychiatric disorders and sex-specific results related to the prenatal Superstorm Sandy hurricane exposure. We comment on the various issues related to the paper below but will not respond to comments regarding the press coverage of this article, which we think are beyond the scope of this commentary., (© 2023 Association for Child and Adolescent Mental Health.)

Competing Interests: The authors report no financial relationships with commercial interests.

Although cannabis is a naturally occurring plant with a long history of use by humans, the chemicals it contains, called cannabinoids, can act on the human body in many ways. Use of cannabis during important periods of development, such as during pregnancy and adolescence, can have a long-lasting impact on the way the brain forms and develops its systems to control emotions and other functions. This article gives an overview of some of the effects of cannabinoids on the developing brain, before birth and as teenagers, and provides information about how young people can prevent or minimize the negative effects of cannabis on their brains., Competing Interests: CONFLICT OF INTEREST: KG has provided consultation to Jazz Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Opioid use disorder (OUD) is influenced by genetic and environmental factors. While recent research suggests epigenetic disturbances in OUD, this is mostly limited to DNA methylation (5mC). DNA hydroxymethylation (5hmC) has been widely understudied. We conducted a multi-omics profiling of OUD in a male cohort, integrating neuronal-specific 5mC and 5hmC as well as gene expression profiles from human postmortem orbitofrontal cortex (OUD = 12; non-OUD = 26). Single locus methylomic analysis and co-methylation analysis showed a higher number of OUD-associated genes and gene networks for 5hmC compared to 5mC; these were enriched for GPCR, Wnt, neurogenesis, and opioid signaling. 5hmC marks also showed a higher correlation with gene expression patterns and enriched for GWAS of psychiatric traits. Drug interaction analysis revealed interactions with opioid-related drugs, some used as OUD treatments. Our multi-omics findings suggest an important role of 5hmC and reveal loci epigenetically dysregulated in OFC neurons of individuals with OUD., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Growing evidence shows an association between in utero exposure to natural disasters and child behavioral problems, but we still know little about the development of specific psychopathology in preschool-aged children., Methods: Preschool children (n = 163, mean age = 3.19, 85.5% racial and ethnic minorities) and their parents (n = 151) were evaluated annually at ages 2-5 to assess the emergence of psychopathology using the Preschool Age Psychopathological Assessment (PAPA), a parent-report structured diagnostic interview developed for preschool-age children. Sixty-six (40.5%) children were exposed to Sandy Storm (SS) in utero and 97 (59.5%) were not. Survival analysis evaluated patterns of onset and estimated cumulative risks of psychopathology among exposed and unexposed children, in total and by sex. Analyses were controlled for the severity of objective and subjective SS-related stress, concurrent family stress, and demographic and psychosocial confounders, such as maternal age, race, SES, maternal substance use, and normative prenatal stress., Results: Exposure to SS in utero was associated with a substantial increase in depressive disorders (Hazard Ratio (HR) = 16.9, p = .030), anxiety disorders (HR = 5.1, p < .0001), and attention-deficit/disruptive behavioral disorders (HR = 3.4, p = .02). Diagnostic rates were elevated for generalized anxiety disorder (GAD; HR = 8.5, p = .004), attention-deficit/hyperactivity disorder (ADHD; HR = 5.5, p = .01), oppositional-defiant disorder (ODD; HR = 3.8, p = .05), and separation-anxiety disorder (SAD; HR = 3.5, p = .001). Males had distinctively elevated risks for attention-deficit/disruptive behavioral disorders (HR = 7.8, p = .02), including ADHD, CD, and ODD, whereas females had elevated risks for anxiety disorders (HR = 10.0, p < .0001), phobia (HR = 2.8, p = .02) and depressive disorders (HR = 30.0, p = .03), including SAD, GAD, and dysthymia., Conclusions: The findings demonstrate that in utero exposure to a major weather-related disaster (SS) was associated with increased risk for psychopathology in children and provided evidence of distinct psychopathological outcomes as a function of sex. More attention is needed to understand specific parent, child, and environmental factors which account for this increased risk, and to develop mitigation strategies., (© 2022 Association for Child and Adolescent Mental Health.)

Opioid use disorder (OUD) looms as one of the most severe medical crises facing society. More effective therapeutics will require a deeper understanding of molecular changes supporting drug-taking and relapse. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNA-seq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following abstinence, and relapse. Bioinformatics analysis of this rich dataset identified numerous patterns of transcriptional regulation, with both region-specific and pan-circuit biological domains affected by heroin. Integration of RNA-seq data with OUD-relevant behavioral outcomes uncovered region-specific molecular changes and biological processes that predispose to OUD vulnerability. Comparisons with human OUD RNA-seq and genome-wide association study data revealed convergent molecular abnormalities and gene candidates with high therapeutic potential. These studies outline molecular reprogramming underlying OUD and provide a foundational resource for future investigations into mechanisms and treatment strategies.

Despite the belief that cannabis is relatively harmless, exposure during adolescence is associated with increased risk of developing several psychopathologies in adulthood. In addition to the high levels of use amongst teenagers, the potency of ∆-9-tetrahydrocannabinol (THC) has increased more than fourfold compared to even twenty years ago, and it is unclear whether potency influences the presentation of THC-induced behaviors. Expanded knowledge about the impact of adolescent THC exposure, especially high dose, is important to delineating neural networks and molecular mechanisms underlying psychiatric risk. Here, we observed that repeated exposure to low (1.5 mg/kg) and high (5 mg/kg) doses of THC during adolescence in male rats produced divergent effects on behavior in adulthood. Whereas low dose rats showed greater sensitivity to reward devaluation and also self-administered more heroin, high dose animals were significantly more reactive to social isolation stress. RNA sequencing of the basolateral amygdala, a region linked to reward processing and stress, revealed significant perturbations in transcripts and gene networks related to synaptic plasticity and HPA axis that were distinct to THC dose as well as stress. In silico single-cell deconvolution of the RNAseq data revealed a significant reduction of astrocyte-specific genes related to glutamate regulation in stressed high dose animals, a result paired anatomically with greater astrocyte-to-neuron ratios and hypotrophic astrocytes. These findings emphasize the importance of dose and behavioral state on the presentation of THC-related behavioral phenotypes in adulthood and dysregulation of astrocytes as an interface for the protracted effects of high dose THC and subsequent stress sensitivity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Early-life adverse experiences can elevate the magnitude of the risk of developmental psychopathology, but the potential synergistic effects of multiple factors have not been well studied., Aims: To determine whether prenatal exposures to maternal stress (Superstorm Sandy) and maternal cannabis use synergistically alter the risk of developmental psychopathology., Method: The study included 163 children (53.4% girls), longitudinally tracked (ages 2-5 years) in relation to the effects of two early-life adverse exposures (Superstorm Sandy and maternal cannabis use). Offspring were grouped by exposure status (neither, only maternal cannabis use, only Superstorm Sandy or both). DSM-IV disorders for offspring were derived from structured clinical interviews; caregiver-reported ratings of family stress and social support were also assessed., Results: A total of 40.5% had been exposed to Superstorm Sandy and 24.5% to maternal cannabis use. Offspring exposed to both ( n = 13, 8.0%), relative to those exposed to neither, had a 31-fold increased risk of disruptive behavioural disorders (DBDs) and a seven-fold increased risk of anxiety disorders. The synergy index demonstrated that offspring with two exposures had synergistic elevation in risk of DBDs (synergy index, 2.06, P = 0.03) and anxiety disorders (synergy index, 2.60, P = 0.004), compared with the sum of single risks. Offspring with two exposures had the highest parenting stress and lowest social support., Conclusions: Our findings are consistent with the double-hit model suggesting that offspring with multiple early-life adverse exposures (Superstorm Sandy and maternal cannabis use) have synergistically increased risks of mental health problems. Given the increasing frequency of major natural disasters and cannabis use, especially among women under stress, these findings have significant public health implications.

Background: Cannabis use suppresses the endocannabinoid system in healthy individuals. However, the association between cannabis use with the endocannabinoid system is understudied in individuals with psychosis despite the high rate of cannabis use in these individuals., Methods: We enrolled 83 individuals who were admitted to an inpatient psychiatric unit with psychotic presentations, and measured their plasma levels of main endocannabinoids, Anandamide (AEA) and 2-Acylglycerol (2-AG), and endocannabinoid related compounds, Palmitoylethanolamine, and N-oleoylethanolamine. Cannabis use was assessed with urine toxicology and frequency of cannabis use was assessed using self-reported questionnaires. The Positive and Negative Syndrome Scale was used to assess the severity of psychotic symptoms., Results: Overall, we had 38 individuals in cannabis positive group (CN+) and 45 individuals in cannabis negative group (CN-). Compared to CN-, CN+ group had lower plasma levels of AEA, which remained significant after controlling for age, gender, race/ethnicity, and use of other drugs., Conclusion: Cannabis use is associated with low plasma AEA levels in individuals with psychosis, which is in the same line with reported suppressive effects of cannabis on the endocannabinoid system in healthy individuals. Further studies are needed to investigate the clinical significance of this finding.

Introduction: DNA methylation (DNAm), an epigenetic mechanism, has been associated with opioid use disorder (OUD) in preclinical and human studies. However, most of the studies have focused on DNAm at CpG sites. DNAm at non-CpG sites (mCpHs, where H indicates A, T, or C) has been recently shown to have a role in gene regulation and to be highly abundant in neurons. However, its role in OUD is unknown. This work aims to evaluate mCpHs in the human postmortem orbital frontal cortex (OFC) in the context of OUD., Methods: A total of 38 Postmortem OFC samples were obtained from the VA Brain Bank (OUD = 12; Control = 26). mCpHs were assessed using reduced representation oxidative bisulfite sequencing in neuronal nuclei. Differential analysis was performed using the "methylkit" R package. Age, ancestry, postmortem interval, PTSD, and smoking status were included as covariates. Significant mCpHs were set at q -value < 0.05. Gene Ontology (GO) and KEGG enrichment analyses were performed for the annotated genes of all differential mCpH loci using String, ShinyGO, and amiGO software. Further, all annotated genes were analyzed using the Drug gene interaction database (DGIdb)., Results: A total of 2,352 differentially methylated genome-wide significant mCpHs were identified in OUD, mapping to 2,081 genes. GO analysis of genes with differential mCpH loci showed enrichment for nervous system development ( p -value = 2.32E-19). KEGG enrichment analysis identified axon guidance and glutamatergic synapse (FDR 9E-4-2.1E-2). Drug interaction analysis found 3,420 interactions between the annotated genes and drugs, identifying interactions with 15 opioid-related drugs, including lofexidine and tizanidine, both previously used for the treatment of OUD-related symptoms., Conclusion: Our findings suggest a role of mCpHs for OUD in cortical neurons and reveal important biological pathways and drug targets associated with the disorder., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nagamatsu, Rompala, Hurd, Núñez-Rios, Montalvo-Ortiz and Traumatic Stress Brain Research Group.)

Importance: Although perceived as relatively harmless and nonaddictive, adolescent cannabis use significantly increases the likelihood of developing cannabis use disorder in adulthood, especially for high-potency cannabis. Risky decision-making is associated with chronic cannabis use, but given confounds of human studies, it remains unclear whether adolescent cannabis exposure and Δ9-tetrahydrocannabinol (THC) potency specifically predicts risky decision-making or influences cognitive response to the drug later in life., Objective: To leverage a human data set of cannabis users and a rat model to evaluate the long-term outcomes of adolescent THC exposure on adult decision-making and impulse control., Design, Setting, and Participants: This translational rat study tested the link between adolescent THC exposure and adulthood decision-making. A reanalysis of a previously published dataset of human chronic cannabis users was conducted to evaluate decision-making phenotypes. Computational modeling assessed the human and animal results in a single framework. Data were collected from 2017 to 2020 and analyzed from 2020 to 2022., Main Outcomes and Measures: Decision-making was measured by the Iowa Gambling Task (IGT) and Rat Gambling Task (rGT). Impulse control was assessed in the rat model. Computational modeling was used to determine reward and punishment learning rates and learning strategy used by cannabis users and THC-exposed rats. Cell-specific molecular measures were conducted in the prefrontal cortex and amygdala., Results: Of 37 participants, 24 (65%) were male, and the mean (SD) age was 33.0 (8.3) years. Chronic cannabis users (n = 22; mean [SE] IGT score, -5.182 [1.262]) showed disadvantageous decision-making compared with controls (n = 15; mean [SE] IGT score, 7.133 [2.687]; Cohen d = 1.436). Risky choice was associated with increased reward learning (mean [SE] IGT score: cannabis user, 0.170 [0.018]; control, 0.046 [0.008]; Cohen d = 1.895) and a strategy favoring exploration vs long-term gains (mean [SE] IGT score: cannabis user, 0.088 [0.012]; control, 0.020 [0.002]; Cohen d = 2.218). Rats exposed to high-dose THC but not low-dose THC during adolescence also showed increased risky decision-making (mean [SE] rGT score: vehicle, 46.17 [7.02]; low-dose THC, 69.45 [6.01]; high-dose THC, 21.97 [11.98]; Cohen d = 0.433) and elevated reward learning rates (mean [SE] rGT score: vehicle, 0.17 [0.01]; low-dose THC, 0.10 [0.01]; high-dose THC, 0.24 [0.06]; Cohen d = 1.541) during task acquisition. These animals were also uniquely susceptible to increased cognitive impairments after reexposure to THC in adulthood, which was correlated with even greater reward learning (r = -0.525; P < .001) and a shift in strategy (r = 0.502; P < .001), similar to results seen in human cannabis users. Molecular studies revealed that adolescent THC dose differentially affected cannabinoid-1 receptor messenger RNA expression in the prelimbic cortex and basolateral amygdala in a layer- and cell-specific manner. Further, astrocyte glial fibrillary acidic protein messenger RNA expression associated with cognitive deficits apparent with adult THC reexposure., Conclusions and Relevance: In this translational study, high-dose adolescent THC exposure was associated with cognitive vulnerability in adulthood, especially with THC re-exposure. These data also suggest a link between astrocytes and cognition that altogether provides important insights regarding the neurobiological genesis of risky cannabis use that may help promote prevention and treatment efforts.

Background: An oral route of administration for tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD) eliminates the harmful effects of smoking and has potential for efficacious cannabis delivery for therapeutic and recreational applications. We investigated the pharmacokinetics of CBD, Δ 9 -THC, 11-OH-THC, and 11-nor-9-carboxy-Δ 9 -THC (THC-COOH) in a novel oral delivery system, Solutech™, compared to medium-chain triglyceride-diluted cannabis oil (MCT-oil) in a healthy population. Materials and Methods: Thirty-two participants were randomized and divided into two study arms employing a comparator-controlled, parallel-study design. To evaluate the pharmacokinetics of Δ 9 -THC, CBD, 11-OH-THC, and THC-COOH, blood was collected at pre-dose ( t =0) and 10, 20, 30, and 45, min and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 48 h post-dose after a single dose of Solutech (10.0 mg Δ 9 -THC, 9.76 mg CBD) or MCT (10.0 mg Δ 9 -THC, 9.92 mg CBD). Heart rate and blood pressure were measured at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 h. Relationships between cannabis use history, body mass index, sex, and pharmacokinetic parameters were investigated. Safety was assessed before and at 48 h post-acute dose. Results: Acute consumption of Solutech provided a significantly greater maximum concentration (C max ), larger elimination and absorption rate constants, faster time to C max and lag time, and half-life for all analytes compared to MCT-oil ( p <0.001). In addition, cannabis use history had a significant influence on the pharmacokinetic parameters of CBD, Δ 9 -THC, 11-OH-THC, and THC-COOH. On average, participants with later age of first use had higher Δ 9 -THC, CBD, and THC-COOH C max and later time-to-C max and half-life for Δ 9 -THC, CBD, THC-COOH, and 11-OH-THC than those with earlier age of first use ( p ≤0.032). Those with more years of recreational cannabis use had higher area under the curve for Δ 9 -THC and CBD, C max for CBD, and longer 11-OH-THC half-life than those with less ( p ≤0.048). Conclusion: This study demonstrated that consumption of Solutech enhanced most pharmacokinetics parameters measured compared to MCT-oil. Participant's cannabis use history, including their age of first use and number of years using cannabis significantly impacted pharmacokinetic parameters investigated. Acute consumption of both products was found to be safe and well tolerated. The results suggest that Solutech may optimize bioavailability from cannabis formulations.

The current study investigated 304 children from a longitudinal project (the Stress in Pregnancy (SIP) Study) who were exposed and unexposed to Superstorm Sandy ("Sandy") in utero. They were prospectively followed from 2 to 6 years of age and their clinical and adaptive behaviors were assessed annually. Using a hierarchical linear model, the study found that in utero Sandy exposure was associated with greater clinical (anxiety, depression, and somatization) and lower adaptive behaviors (social skills and functional communication) at age 2 years. However, the trajectories were notably different between the two groups. Anxiety increased more rapidly among the exposed than unexposed group at ages 2-4, and depression increased only among the exposed. In contrast, social skills and functional communication were lower in exposed compared to unexposed children at age 2, but quickly increased and exceeded the capacities of unexposed children by age 3. The findings confirm that prenatal Sandy exposure is not only associated with an increase in anxiety, depression, and somatization in offspring, but also with greater adaptive skills as the children got older. Our study demonstrates that while children who have experienced stress in utero demonstrate elevated suboptimal clinical behaviors related to affective disorders, they nevertheless have the potential to learn adaptive skills.

Introduction: Opioid use disorder (OUD) is a major public health crisis worldwide. Patients with OUD inevitably experience withdrawal symptoms when they attempt to taper down on their current opioid use, abstain completely from opioids, or attempt to transition to certain medications for opioid use disorder. Acute opioid withdrawal can be debilitating and include a range of symptoms such as anxiety, pain, insomnia, and gastrointestinal symptoms. Whereas acute opioid withdrawal only lasts for 1-2 weeks, protracted withdrawal symptoms can persist for months after the cessation of opioids. Insufficient management of opioid withdrawal often leads to devastating results including treatment failure, relapse, and overdose. Thus, there is a critical need for cost-effective, nonopioid medications, with minimal side effects to help in the medical management of opioid withdrawal syndrome. We discuss the potential consideration of cannabidiol (CBD), a nonintoxicating component of the cannabis plant, as an adjunctive treatment in managing the opioid withdrawal syndrome. Materials and Methods: A review of the literature was performed using keywords related to CBD and opioid withdrawal syndrome in PubMed and Google Scholar. A total of 144 abstracts were identified, and 41 articles were selected where CBD had been evaluated in clinical studies relevant to opioid withdrawal. Results: CBD has been reported to have several therapeutic properties including anxiolytic, antidepressant, anti-inflammatory, anti-emetic, analgesic, as well as reduction of cue-induced craving for opioids, all of which are highly relevant to opioid withdrawal syndrome. In addition, CBD has been shown in several clinical trials to be a well-tolerated with no significant adverse effects, even when co-administered with a potent opioid agonist. Conclusions: Growing evidence suggests that CBD could potentially be added to the standard opioid detoxification regimen to mitigate acute or protracted opioid withdrawal-related symptoms. However, most existing findings are either based on preclinical studies and/or small clinical trials. Well-designed, prospective, randomized-controlled studies evaluating the effect of CBD on managing opioid withdrawal symptoms are warranted.

Background: Cannabis remains one of the most widely abused drugs during pregnancy. In utero exposure to its principal psychoactive component, Δ 9 -tetrahydrocannabinol (THC), can result in long-term neuropsychiatric risk for the progeny. This study investigated epigenetic signatures underlying these enduring consequences., Methods: Rat dams were exposed daily to THC (0.15 mg/kg) during pregnancy, and adult male offspring were examined for reward and depressive-like behavioral endophenotypes. Using unbiased sequencing approaches, we explored transcriptional and epigenetic profiles in the nucleus accumbens (NAc), a brain area central to reward and emotional processing. An in vitro CRISPR (clustered regularly interspaced short palindromic repeats) activation model coupled with RNA sequencing was also applied to study specific consequences of epigenetic dysregulation, and altered molecular signatures were compared with human major depressive disorder transcriptome datasets., Results: Prenatal THC exposure induced increased motivation for food, heightened learned helplessness and anhedonia, and altered stress sensitivity. We identified a robust increase specific to males in the expression of Kmt2a (histone-lysine N-methyltransferase 2A) that targets H3K4 (lysine 4 on histone H3) in cellular chromatin. Normalizing Kmt2a in the NAc rescued the motivational phenotype of prenatally THC-exposed animals. Comparison of RNA- and H3K4me3-sequencing datasets from the NAc of rat offspring with the in vitro model of Kmt2a upregulation revealed overlapping, significant disturbances in pathways that mediate synaptic plasticity. Similar transcriptional alterations were detected in human major depressive disorder., Conclusions: These studies provide direct evidence for the persistent effects of prenatal cannabis exposure on transcriptional and epigenetic deviations in the NAc via Kmt2a dysregulation and associated psychiatric vulnerability., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Substance use disorders (SUDs) are frequently stigmatized by society. However, overcoming stigmas to effectively treat SUDs requires acknowledging the developmental path of neural vulnerability. These vulnerabilities begin long before adulthood, providing opportunities to change the trajectory before the disorder becomes entrenched. This article raises attention to reversible epigenetic underpinnings of this vulnerability., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context: Synthetic cannabinoids (SCs) are a structurally heterogenous synthetic class of drugs of abuse. The objective was to describe the incidence of acute respiratory failure in Emergency Department (ED) patients with confirmed SC exposure, and to investigate the association between SC overdose with respiratory failure compared to non-SC overdose., Methods: This was an observational cohort of ED patients ≥18 years with suspected cannabinoid overdose between 2015 and 2020 at two tertiary-care hospitals. Patient serum was analyzed via liquid chromatography/quadrupole time-of-flight mass spectrometry using a library with >800 drugs including novel psychoactive substances. The primary outcome was acute respiratory failure., Discussion: Of 83 patients with suspected cannabinoid overdose, there were 29 confirmed SC overdoses: 5 F-MDMB-PICA ( n  = 18) and its metabolite 5OH-MDMB-PICA ( n  = 16), ADB-FUBINACA ( n  = 4), AB-CHIMINACA ( n  = 4), AB-FUBINACA ( n  = 1), AB-PINACA ( n  = 1), MDMB-4en-PINACA ( n  = 1), and 4 F-MDMB-BINACA ( n  = 1). Overall, incidence of acute respiratory failure was 31.3% (95%CI 21.6-42.4). Compared to non-SC overdose, confirmed SC overdose was significantly associated with respiratory failure (25.0% SC vs. 4.2% non-SC, p  = 0.05)., Conclusion: This study demonstrates that SCs are associated with respiratory failure. Since respiratory depression is a potentially lethal adverse effect of SC overdose, future research is warranted.

Objective: Substance-use is a prevalent presentation to the emergency department (ED); however, the clinical characterization of patients who are treated and discharged without admission for further treatment is under-investigated. The study aims to define and characterize the clinical profiles of this patient population., Methods: Patients' presentations were examined by clinical data mining (chart review) of ED records of substance use-related events of individuals discharged without admission for further treatment. Records (N = 199) from three major hospitals in New York City from March and June 2017 were randomly sampled with primary diagnosis of alcohol, opioid-related and other psychoactive substance-use presentations. Qualitative thematic coding of clinical presentation with inter-rater reliability was performed. Quantitative distinctive validity tested independence through Pearson's chi-squared and analysis of variance using Fisher's F-test., Results: Six distinct clinical profiles were identified, including, High Utilizers (chronically intoxicated with comorbid health conditions) (36.7%), Single Episode (20.1%), Service Request (14.1%), Altered Mental Status (13.6%), Overdose (9.0%), and Withdrawal (7.5%). The profiles differed (p < 0.05) in age, housing status, payor, mode of arrival, referral source, index visit time, prescribed treatment, triage acuity level, psychiatric history, and medical history. Differences (p < 0.05) between groups across clinical profiles in age and pain level at triage were observed., Conclusions: The identified clinical profiles represent the broad spectrum and complex nature of substance use-related ED utilization, highlighting critical factors of psychosocial and mental-health comorbidities. These findings provide a preliminary foundation to support person-centered interventions to decrease substance use-related ED utilization and to increase engagement/linkage of patients to addiction treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of interests KH has been supported by the Esther Ting Memorial Professorship at Stanford University School of Medicine and research grants from the US Veterans Administration Health Services Research and Development Service (RCS 04-141-3, HX-12-001, and HX002714-01A2), the US National Institute on Drug Abuse (3UG1 DA015815-17S4 and 2UG1DA015815-19), the US Food and Drug Administration, Wu Tsai Neurosciences Institute, the Silicon Valley Community Foundation, the County of Santa Clara California, and the American Board of Family Medicine. He has received speaking honoraria and travel expenses from the American College of Medical Toxicology, Arizona State University, Barclays Bank, Caron Foundation, the University of Florida, the New York Museum of Modern Art, Syracuse University, West Virginia University School of Medicine, and the West Virginia Medical Professionals Health Program. He has received writing honoraria or royalties from the Association of Psychological Science, American Academy of Political and Social Science, Brookings Institution, Cambridge University Press, and Washington Monthly. He has been a paid consultant to AELIS Pharma, Harvard Medical School, and Harvard University Press. CLS has been employed by Stanford University, the University of California, Los Angeles (UCLA), the Los Angeles County Department of Public Health, Heluna Health, and the Los Angeles LGBT Center. She has received research funding or stipends from the US National Institute on Drug Abuse (K01DA050771, T32DA035165), the RAND Opioid Policy Tools and Information Center), Wu Tsai Neurosciences Institute, and UCLA David Geffen School of Medicine, and speaking honoraria or travel expenses from Emory University, New York University, UCLA, the University of North Carolina at Chapel Hill, the University of Southern California, the University of Pittsburgh, the University of Chicago, the University of Western Ontario, the Nevada State Medical Association, RAND, the University of California, Irvine, the US Centers for Disease Control and Prevention, College on Problems of Drug Dependence, the Conference on Retroviruses and Opportunistic Infections, HIV Research for Prevention, Addiction Health Services Research, and the American Psychopathological Association. CMA has been supported by the Arnold School of Public Health at the University of South Carolina, and by research grants from the US National Institute on Drug Abuse (R01DA034634, K01DA041628, U2CDA050097, R01DA049776, and R01DA052425), the US National Institute on Alcoholism and Alcohol Abuse (R01AA029097 and R01AA029821), and the South Carolina Department of Alcohol and Other Drug Abuse Services, and has been a paid consultant to the Robert Wood Johnson Foundation, RTI International, the Medical University of South Carolina, the State of Pennsylvania Department of Public Health, and the State of Illinois Division of Health Care and Family Services. ASBB has been supported by grants from the US National Institutes for Health (R01 DA045705), the US Veterans Health Administration (IIR 13-322 and C19 21-278), the US Centers for Disease Control and Prevention (U01CE002780), Blue Cross Blue Shield of Michigan, the US Department of Defense, the Patient-Centered Outcomes Research Institute, the Michigan Health Endowment Fund, and the Substance Abuse and Mental Health Services Administration via sub-contracts from the Michigan Department of Health and Human Services, has received speaker honoraria or travel expenses from the Illinois Health and Hospital Association, the International Summit on Suicide Research, the Washington State Department of Labor & Industries, the American Psychopathological Association, and the High Intensity Drug Trafficking Area program, has been paid as a consultant by New York University, and has received products from Fitbit at a reduced cost and Headspace for free for research purposes. MLB has been supported by research grants from the US Department of Veterans Affairs and the US National Institute on Drug Abuse (R37-DA15612), and a Koret Foundation gift for Smart Cities and Digital Living, has received travel expenses from the University of Maryland, the University of Auckland, Massachusetts Institute of Technology, the European Working Group on Stochastic Modeling, INSEAD, the University of Michigan, and the University of Oklahoma, and has been a paid consultant to Compass Lexecon and DE Shaw. JPC has received a National Science Foundation EAGER Grant on Detecting and Disrupting Illicit Supply Networks via Traffic Distribution Systems, is a consultant to the RAND Corporation's Drug Policy Research Center, has consulted with or received honoraria from the Actis—Norwegian Policy Network on Alcohol and Drugs, the Arnold Foundation, Bank of Montreal, Boston University, the Foreign Affairs, Justice Research and Statistics Association, Lisbon Addictions Conference, Massachusetts Institute of Technology, National Affairs, the National Institute of Justice, Oxford University Press, Pew, PIRE, the Russell Sage Foundation, Springer Verlag, Stanford University, the US State Department, Texas Research Society on Alcoholism, the US Veteran's Administration, Washington Monthly, and the WT Grant Foundation. JHC has received research support or funding from the US National Institutes of Health and National Library of Medicine (R56LM013365), the Gordon and Betty Moore Foundation (GBMF8040), the US National Science Foundation (SPO181514); Google (SPO13604), the Stanford Clinical Excellence Research Center, the Stanford Department of Medicine and Department of Pathology, and the Stanford Aging and Ethnogeriatrics Research Center (P30AG059307), which is part of the Resource Centers for Minority Aging Research programme led by the US National Institute on Aging at the National Institutes of Health, is the co-founder of Reaction Explorer (which develops and licenses organic chemistry education software), and has been paid consulting or speaker fees by the US National Institute of Drug Abuse Clinical Trials Network, Tuolc, Roche, and Younker Hyde MacFarlane. M-FC has served as president of the Carnegie Endowment for International Peace, a justice of the Supreme Court of California, the Herman Phleger Professor at Stanford Law School, a distinguished visiting jurist at the New York University School of Law, the Castle Distinguished Lecturer in Ethics, Politics, and Economics at Yale University, a member of the President & Fellows of Harvard College (the Harvard Corporation), a member of the board of directors of the William and Flora Hewlett Foundation, a member of the Council of the American Law Institute, chair of the board of directors of the Center for Advanced Study in the Behavioral Sciences, chair of the advisory board of the Seed Initiative at the Stanford Graduate School of Business, and a member of the advisory board at the Stanford Human-Centered Artificial Intelligence Institute. His work has been supported by Stanford Law School and by a grant from the Stanford Human-Centered Artificial Intelligence Institute, and he was previously chair of the advisory board of the AI Now Institute at New York University. YLH has received research grants from the US National Institute on Drug Abuse (DA050323, DA048613, DA008227, DA043247, DA030359, DA037317, and DA15446), research funding from GW Pharmaceuticals, speaking honoraria or travel expenses, or both, from the University of North Carolina, the American Society for the Advancement of Science, the Society for Neuroscience Public Education & Communication Committee, Washington University in St Louis, Temple University, Tufts School of Medicine, Indiana University, the American College of Neuropsychopharmacology, the Iowa Neuroscience Institute, the Franklin Institute, State University of New York Upstate Medical University, the Canadian Consortium for the Investigation of Cannabinoids, the University of Michigan, Cold Spring Harbor Laboratory, the US National Institutes of Health, Penn State Hershey College of Medicine, the US National Academy of Medicine, the Mediterranean Neuroscience Society, the Wu Tsai Neurosciences Institute, Society of Biological Psychiatry, International College of Neuropharmacology, the Federation of European Neuroscience Societies, Gordon Research Conference, the National Institutes of Health Center for Scientific Research Council, and the Society of Neuroscience. DNJ has received research grants from the Canadian Institutes for Health Research and the Ontario Ministry of Health, financial support from the departments of medicine at both the University of Toronto and Sunnybrook Health Sciences Centre, travel expenses or speaking honoraria from Dalhousie University, the University of Ottawa, the University of Saskatchewan, the University of Calgary, the Bloomberg Johns Hopkins School of Public Health, the American College of Physicians, the University of Alabama at Birmingham, the American Society of Nephrology, the Canadian Society of Internal Medicine, the Canadian Anesthesiologists' Society, The Canadian Society of Obstetricians and Gynecologists, the Western Canada Addiction Forum, and the Canadian House of Commons Standing Committee on Health, and payment for expert witness testimony from (and has been retained by) Sanis, a generic drug manufacturer and distributor to provide advice related to an ongoing Canadian class action, and is a volunteer member of Physicians for Responsible Opioid Prescribing. HKK has been supported by grants from the Robert Wood Johnson Foundation (77667, 74275, and 73359), the John Templeton Foundation (52125), the JPB Foundation (1085 and 439), and the Association of State and Territorial Health Officers (1584), has received honoraria from Jefferson University, Jefferson Health, the Perelman School of Medicine at the University of Pennsylvania, MaineHealth Center for Tobacco Independence, Harvard University Memorial Church, the Association of State and Territorial Health Officials, the University of Wisconsin Medical School, Wake Forest Baptist Health (in partnership with Shaw University), the Robert Wood Johnson Foundation advisory committee, the American College of Gastroenterology, and Tufts University School of Medicine, has been a consultant to the Commonwealth Fund, and is a member of the Community COVID Coalition Advisory Group, Phillips Academy Public Health Expert Advisory Panel, the Policy Advisory Group, the board of the Bipartisan Policy Center, the Palliative and Advanced Illness Research Center External Advisory Board (at the Perelman School of Medicine), the American Cancer Society Eastern New England Area Council of Advisors, the American University of Beirut International Advisory Council, the US National Advisory Board, the Culture of Health Year in Review Advisory Committee and Culture of Health as a Business Imperative Initiative of the Robert Wood Johnson Foundation, the editorial board of the Journal of the American Medical Association, the New England Donor Services board of trustees, the Josiah Macy Jr Foundation board of directors, and the Lancet–O'Neill Institute, Georgetown University Commission on Global Health and the Law. EEK has received research funding from the US Department of Veterans Affairs Health Services Research and Development (COR 19-489, 1I01HX003063-01A1, 5I01HX001752-05, 5I01HX002737-02, 5I01HX001288-05, and 5I01HX000911-06), the Patient Centered Outcomes Research Institute (OPD-1511-33052), the US National Center for Complementary and Integrative Health (5R01AT008387-04, 5UH3AT009761- 04/5UG3AT009761-02, and 4UH3AT009765-03/5UG3AT009765-02), and the US National Institute of Diabetes and Digestive and Kidney Diseases (1U01DK123816-01), and travel expenses from the law firm Nix Patterson representing the state of Oklahoma (to serve as an expert witness in support of the state's litigation against opioid manufacturers), the American Society of Health-System Pharmacists, the Association of Academic Physiatrists, the Australian Pain Society, the Cleveland VA Medical Research and Education Foundation, the Duke-Margolis Center for Health Policy, the Foundation for Medical Excellence, the Foundation for Opioid Response Efforts, the Friends of VA Medical Care and Health Research, the Hennepin Healthcare Research Institute, the Indiana Institute for Medical Research, the US National Academies of Medicine, the US National Center for Complementary and Integrative Health, the National Governors Association, the North American Spine Society, the Patient Centered Outcomes Research Institute at Stanford University, the US Food and Drug Administration, and the Washington State Department of Labor & Industries. AL has received consulting fees for her work as a medical expert witness in federal and state litigation against opioid manufacturers, distributors, and pharmacies, book royalties from Johns Hopkins University Press and Dutton Penguin Random House, speaking honoraria or travel expenses, or both, from the Vanderbilt University School of Medicine, the Ohio State University School of Medicine, the University of Kansas School of Medicine (sponsorship of the Alpha Omega Alpha Visiting Professorship), the Oregon Pain Guidance, the Indiana Prosecuting Attorneys Council, the Perrin's Opioid Litigation Conference, the Public Funds Forum, the Baton Rouge Health District, the Montrose Colorado Annual Continuing Medical Education Conference, the PerformRX Pharmacy Benefits Manager Annual Conference, the American Academy of Psychiatry and the Law, the Psych Congress, the 69th Annual Canadian Refresher Course for Family Physicians, the Ohio State University Inter-Professional Summit, the University of Texas, the Geminus Community Partners Annual Conference of Indiana, the National Council on Alcoholism and Drug Abuse, the Stanford Sierra Camp Womens' Alumni Wellness Retreat, the American Psychiatric Association, the Association for Medical Education and Research in Substance Abuse, and the Southwestern Gynecologic Assembly. SCM has been supported by the Redlich Professorship and the Rosekrans Pain Research Endowment Fund at Stanford University School of Medicine and research grants awarded to Stanford University from the US National Institutes of Health (R61NS118651, R03HD094577, R01DA045027, R01NS109450, R01AT008561, K24DA02926207, R01DA035484, and P01AT00665105), the Patient Centered Outcomes Research Institute (PCORI OPD-1610- 370707), the Stanford Wu Tsai Neurosciences Institute, and the University of California, San Francisco–Stanford Center of Excellence in Regulatory Science and Innovation (FDA) (2U01FD005978-06), has received speaking honoraria or travel expenses from Walter Reed, Harvard University, the American Academy of Pain Medicine, Washington University, the US Food and Drug Administration, the US National Institutes of Health, the US National Institute of Neurological Disorders and Stroke, the University of Washington, George Washington University, New York University, Weill Cornell Medical College, Duke University, the University of Utah, the World Institute of Pain, and the Canadian Pain Society, has received payment for testimony (unrelated to opioids) from Lauria Tokunaga Gates and Linn, and has received payment for consulting (unrelated to opioids) from the American Society of Anesthesiology; Favros Law; Fain Anderson VanDerhoef Rosendahl O'Halloran Spillane; Cox, Wootton, Lerner, Griffin & Hansen; Lewis Brisbois Bisgaard & Smith; Muro & Lampe; McCormick Barstow; Schmid & Voiles; and the University of Oklahoma Health Sciences Center. LLO has received travel expenses or honoraria from Cardozo Law School, Claremont McKenna College, Duke University, ETH Zürich, Georgetown University, Harvard University, the Los Angeles Intellectual Property Law Association, Michigan State University, New York University, Northwestern University, the University of Chicago, the University of Houston, the University of Kansas, the University of Nebraska, the University of San Diego, the University of Texas, the University of Villanova, the World Intellectual Property Organization, and Yale University, has received a writing honoraria from the Brookings Institution (to write a policy proposal for the Hamilton Project), and is a paid consultant to the MITRE Corporation (to assist with evaluations of the US Patent and Trademark Office requested by the Department of Commerce). BS has received research support from the US National Institute on Alcohol Abuse and Alcoholism (R01 AA023650 and K23 AA023284), the US National Institute of Drug Abuse (R21 DA043181), the US National Institute of Mental Health (P50MH115838), and the US National Highway Transportation Safety Authority, has received royalties from a software licence to healthStratica, and has several invention disclosures with the University of Pittsburgh for digital behavioral interventions. CT has been supported by the US Department of Veterans Affairs (VA HSR&D IIR 15-298, IIR 18-253, IIR 20-058, and PPO 16-337) and the US National Institutes of Health (NIAAA 1R01AA024136-01).

Our authors, who direct the Addiction Institute for the Mount Sinai Health System in New York City, address the substance-abuse avalanche brought on by the Covid-19 pandemic., (Copyright 2022 The Dana Foundation All Rights Reserved.)

Heroin, a mu agonist, acts through the mu opioid receptor. The mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating an array of splice variants that are conserved from rodent to humans. Increasing evidence suggests that these OPRM1 splice variants are pharmacologically important in mediating various actions of mu opioids, including analgesia, tolerance, physical dependence, rewarding behavior, as well as addiction. In the present study, we examine expression of the OPRM1 splice variant mRNAs in the medial prefrontal cortex (mPFC), one of the major brain regions involved in decision-making and drug-seeking behaviors, of male human heroin abusers and male rats that developed stable heroin-seeking behavior using an intravenous heroin self-administration (SA) model. The results show similar expression profiles among multiple OPRM1 splice variants in both human control subjects and saline control rats, illustrating conservation of OPRM1 alternative splicing from rodent to humans. Moreover, the expressions of several OPRM1 splice variant mRNAs were dysregulated in the postmortem mPFCs from heroin abusers compared to the control subjects. Similar patterns were observed in the rat heroin SA model. These findings suggest potential roles of the OPRM1 splice variants in heroin addiction that could be mechanistically explored using the rat heroin SA model., (© 2020 Wiley Periodicals, Inc.)

Background: Drug addiction is a complex brain disorder that is characterized by craving, withdrawal, and relapse, which can be perpetuated by social stress. Stemming from an acute life event, chronic stress, or trauma in a social context, social stress has a major role in the initiation and trajectory of substance use. Preclinical literature shows that early life stress exposure and social isolation facilitate and enhance drug self-administration. Epidemiological evidence links childhood adversity to increased risk for drug use and demonstrates that cumulative stress experiences are predictive of substance use severity in a dose-dependent manner. Stress and drug use induce overlapping brain alterations leading to downregulation or deficits in brain reward circuitry, thereby resulting in greater sensitization to the rewarding properties of drugs. Though stress in the context of addiction has been studied at the neural level, a gap in our understanding of the neural underpinnings of social stress in humans remains., Methods: We conducted a systematic review of in vivo structural and functional neuroimaging studies to evaluate the neural processes associated with social stress in individuals with substance use disorder. Results were considered in relation to participants' history of social stress and with regard to the effects of social stress induced during the neuroimaging paradigm., Results: An exhaustive search yielded 21 studies that matched inclusion criteria. Social stress induces broad structural and functional neural effects in individuals with substance use disorder throughout their lifespan and across drug classes. A few patterns emerged across studies: (1) many of the brain regions altered in individuals who were exposed to chronic social stress and during acute stress induction have been implicated in addiction networks (including the prefrontal cortex, insula, hippocampus, and amygdala); (2) individuals with childhood maltreatment and substance use history had decreased gray matter or activation in regions of executive functioning (including the medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex), the hippocampal complex, and the supplementary motor area; and (3) during stress-induction paradigms, activation in the anterior cingulate cortex, caudate, and amygdala was most commonly observed., Conclusions/implications: A distinct overlap is shown between social stress-related circuitry and addiction circuitry, particularly in brain regions implicated in drug-seeking, craving, and relapse. Given the few studies that have thoroughly investigated social stress, the evidence accumulated to date needs to be replicated and extended, particularly using research designs and methods that disentangle the effects of substance use from social stress. Future clinical studies can leverage this information to evaluate the impact of exposure to trauma or adverse life events within substance use research. Expanding knowledge in this emerging field could help clarify neural mechanisms underlying addiction risk and progression to guide causal-experimental inquiry and novel prevention and treatment strategies., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

While cannabis is among the most used recreational drugs during pregnancy, the impact of maternal cannabis use (mCB) on fetal and child development remains unclear. Here, we assessed the effects of mCB on psychosocial and physiological measures in young children along with the potential relevance of the in utero environment reflected in the placental transcriptome. Children (∼3 to 6 y) were assessed for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children (BASC-2) survey, and heart rate variability (HRV) at rest and during auditory startle. For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing. Hair hormone analysis revealed increased cortisol levels in mCB children. In addition, mCB was associated with greater anxiety, aggression, and hyperactivity. Children with mCB also showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone. In the placenta, there was reduced expression of many genes involved in immune system function including type I interferon, neutrophil, and cytokine-signaling pathways. Finally, several of these mCB-linked immune genes organized into coexpression networks that correlated with child anxiety and hyperactivity. Overall, our findings reveal a relationship between mCB and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood., Competing Interests: The authors declare no competing interest.

Prenatal stress can lead to long-term adverse effects that increase the risk of anxiety and other emotional disorders in offspring. The in utero underpinnings contributing to such phenotypes remain unknown. We profiled the transcriptome of placental specimens from women who lived through Hurricane Sandy during pregnancy compared to those pregnant during non-Sandy conditions. Following birth, longitudinal assessments were conducted in their offspring during childhood (~3-4 years old) to measure steroid hormones (in hair) and behavioral and emotional problems. This revealed a significant link between prenatal Sandy stress (PNSS) and child HPA dysfunction, evident by altered cortisol, dehydroepiandrosterone (DHEA), and cortisol:DHEA levels. In addition, PNSS was associated with significantly increased anxiety and aggression. These findings coincided with significant reorganization of the placental transcriptome via vascular, immune, and endocrine gene pathways. Interestingly, many of the most prominently altered genes were known to be uniquely expressed in syncytiotrophoblast (STB)-subtype of placental cells and harbored glucocorticoid response elements in promoter regions. Finally, several vascular development- and immune-related placental gene sets were found to mediate the relationship between PNSS and childhood phenotypes. Overall, these findings suggest that natural disaster-related stress during pregnancy reprograms the placental molecular signature, potentially driving long-lasting changes in stress regulation and emotional health. Further examination of placental mechanisms may elucidate the environment's contribution to subsequent risk for anxiety disorders later in life., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Maternal psychosocial stress during pregnancy (MPSP) is a known contributor to maladaptive neurobehavioral development of the offspring; however, the underlying molecular mechanisms linking MPSP with childhood outcome remain largely unknown. Transcriptome-wide gene expression data were generated using RNA-seq from placenta samples collected in a multi-ethnic urban birth cohort in New York City (n = 129). Weighted gene co-expression network analysis (WGCNA) was used to characterize placental co-expression modules, which were then evaluated for their associations with MPSP and infant temperament. WGCNA revealed 16 gene coexpression modules. One module, enriched for regulation of chromosome organization/gene expression, was positively associated with MPSP and negatively associated with Regulatory Capacity (REG), a component of infant temperament. Two other modules, enriched for cotranslational protein targeting and cell cycle regulation, respectively, displayed negative associations with MPSP and positive associations with REG. A module enriched with oxidative phosphorylation/mitochondrial translation was positively associated with REG. These findings support the notion that the placenta provides a functional in utero link between MPSP and infant temperament, possibly through transcriptional regulation of placental gene expression., (© 2021 Federation of American Societies for Experimental Biology.)

Many developmental disorders are thought to arise from an interaction between genetic and environmental risk factors. The Hedgehog (HH) signaling pathway regulates myriad developmental processes, and pathway inhibition is associated with birth defects, including holoprosencephaly (HPE). Cannabinoids are HH pathway inhibitors, but little is known of their effects on HH-dependent processes in mammalian embryos, and their mechanism of action is unclear. We report that the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) induces two hallmark HH loss-of-function phenotypes (HPE and ventral neural tube patterning defects) in Cdon mutant mice, which have a subthreshold deficit in HH signaling. THC therefore acts as a 'conditional teratogen', dependent on a complementary but insufficient genetic insult. In vitro findings indicate that THC is a direct inhibitor of the essential HH signal transducer smoothened. The canonical THC receptor, cannabinoid receptor-type 1, is not required for THC to inhibit HH signaling. Cannabis consumption during pregnancy may contribute to a combination of risk factors underlying specific developmental disorders. These findings therefore have significant public health relevance., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Recent years have been transformational in regard to the perception of the health risks and benefits of cannabis with increased acceptance of use. This has unintended neurodevelopmental implications given the increased use of cannabis and the potent levels of Δ 9 -tetrahydrocannabinol today being consumed by pregnant women, young mothers and teens. In this Review, we provide an overview of the neurobiological effects of cannabinoid exposure during prenatal/perinatal and adolescent periods, in which the endogenous cannabinoid system plays a fundamental role in neurodevelopmental processes. We highlight impaired synaptic plasticity as characteristic of developmental exposure and the important contribution of epigenetic reprogramming that maintains the long-term impact into adulthood and across generations. Such epigenetic influence by its very nature being highly responsive to the environment also provides the potential to diminish neural perturbations associated with developmental cannabis exposure.

The use of opioid drugs and related overdose deaths, which rose to epidemic proportions over the past decade, have been exacerbated by the COVID pandemic, a time of great uncertainty and isolation. Much is known about opioid pharmacology and related neural circuits that, combined with novel emerging neurobiological insights, can help guide new treatment strategies. To view this SnapShot, open or download the PDF., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Overdose of stimulant drugs has been associated with increased risk of adverse cardiovascular events (ACVE), some of which may be ascribed to endothelial dysfunction. The aims of this study were to evaluate biomarkers of endothelial dysfunction in emergency department (ED) patients with acute cocaine overdose and to assess the association between in-hospital ACVE in ED patients with any acute drug overdose. This was a prospective consecutive cohort study over 9 months (2015-2016) at two urban, tertiary-care hospital EDs. Consecutive adults (≥18 years) presenting with suspected acute drug overdose were eligible and separated into three groups: cocaine (n = 47), other drugs (n = 128), and controls (n = 11). Data were obtained from medical records and linked to waste serum specimens, sent as part of routine clinical care, for biomarker analysis. Serum specimens were collected and analyzed using enzyme-linked immunosorbent assay kit for three biomarkers of endothelial dysfunction: (a) endothelin-1 (ET-1), (b) regulated upon activation normal T cell expressed and secreted (RANTES), and (c) soluble intercellular adhesion molecule-1 (siCAM-1). Mean siCAM was elevated for cocaine compared with controls and other drugs (p < .01); however, mean RANTES and ET-1 levels were not significantly different for any drug exposure groups. Receiver operating characteristics curve analysis for prediction of in-hospital ACVE revealed excellent performance of siCAM-1 (area under curve, 0.86; p < .001) but lack of predictive utility for either RANTES or ET-1. These results suggest that serum siCAM-1 is a viable biomarker for acute cocaine overdose and that endothelial dysfunction may be an important surrogate for adverse cardiovascular events following any drug overdose., (© 2020 Society for the Study of Addiction.)

The chromatin landscape of human brain cells encompasses key information to understanding brain function. Here we use ATAC-seq to profile the chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes) from three different brain regions (anterior cingulate cortex, dorsolateral prefrontal cortex, and primary visual cortex) in human postmortem brain samples. We find that chromatin accessibility varies greatly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the largest regional variability. Transcription factor footprinting implicates cell-specific transcriptional regulators and infers cell-specific regulation of protein-coding genes, long intergenic noncoding RNAs and microRNAs. In vivo transgenic mouse experiments validate the cell type specificity of several of these human-derived regulatory sequences. We find that open chromatin regions in glutamatergic neurons are enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Integration of cell-specific chromatin data with a bulk tissue study of schizophrenia brains increases statistical power and confirms that glutamatergic neurons are most affected. These findings illustrate the utility of studying the cell-type-specific epigenome in complex tissues like the human brain, and the potential of such approaches to better understand the genetic basis of human brain function.

Inflammatory abnormalities are well-documented in individuals with chronic psychotic disorders. Particular attention has focused on interleukin-6 (IL-6) and its correlation with psychotic symptom severity. Cannabis use is associated with an increased risk of psychosis and also has immunomodulating properties. It has been hypothesized that inflammatory disturbances are a common underlying pathology between cannabis use and psychosis. We measured inflammatory markers in individuals admitted to a psychiatric unit with acute psychosis who had toxicology positive for natural and/or synthetic cannabinoids (n = 59) compared to patients with negative cannabinoid toxicology (n = 60). Psychosis severity was assessed using the Positive and Negative Syndrome Scale (PANSS). While PANSS scores were similar between groups, cannabinoid-positive participants were more likely to receive pro re nata (PRN or as-needed) medications for agitation in the psychiatric emergency room, particularly synthetic cannabinoid-positive participants. In unadjusted models, cannabinoid-positive participants had lower interferon-γ (IFN-γ) levels (p = 0.046), but this finding was not significant after adjusting for covariates and multiple comparisons. Among cannabinoid-positive participants, IL-6 levels negatively correlated with PANSS total score (p = 0.040), as well as positive (p = 0.035) and negative (p = 0.024) subscales. Results suggest inflammatory alterations among psychotic individuals with comorbid cannabinoid use., (Copyright © 2020. Published by Elsevier B.V.)

The first issue of Nature Reviews Neuroscience was published 20 years ago, in 2000. To mark this anniversary, in this Viewpoint article we asked a selection of researchers from across the field who have authored pieces published in the journal in recent years for their thoughts on notable and interesting developments in neuroscience, and particularly in their areas of the field, over the past two decades. They also provide some thoughts on current lines of research and questions that excite them.

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.

Consumption of high fat, high sugar (western) diets is a major contributor to the current high levels of obesity. Here, we used a multidisciplinary approach to gain insight into the molecular mechanisms underlying susceptibility to diet-induced obesity (DIO). Using positron emission tomography (PET), we identified the dorsal striatum as the brain area most altered in DIO-susceptible rats and molecular studies within this region highlighted regulator of G-protein signaling 4 (Rgs4) within laser-capture micro-dissected striatonigral (SN) and striatopallidal (SP) medium spiny neurons (MSNs) as playing a key role. Rgs4 is a GTPase accelerating enzyme implicated in plasticity mechanisms of SP MSNs, which are known to regulate feeding and disturbances of which are associated with obesity. Compared to DIO-resistant rats, DIO-susceptible rats exhibited increased striatal Rgs4 with mRNA expression levels enriched in SP MSNs. siRNA-mediated knockdown of striatal Rgs4 in DIO-susceptible rats decreased food intake to levels comparable to DIO-resistant animals. Finally, we demonstrated that the human Rgs4 gene locus is associated with increased body weight and obesity susceptibility phenotypes, and that overweight humans exhibit increased striatal Rgs4 protein. Our findings highlight a novel role for involvement of Rgs4 in SP MSNs in feeding and DIO-susceptibility.

There have been dramatic changes worldwide in the attitudes toward and consumption of recreational and medical cannabis. Cannabinoid receptors, which mediate the actions of cannabis, are abundantly expressed in brain regions known to mediate neural processes underlying reward, cognition, emotional regulation and stress responsivity relevant to addiction vulnerability. Despite debates regarding potential pathological consequences of cannabis use, cannabis use disorder is a clinical diagnosis with high prevalence in the general population and that often has its genesis in adolescence and in vulnerable individuals associated with psychiatric comorbidity, genetic and environmental factors. Integrated information from human and animal studies is beginning to expand insights regarding neurobiological systems associated with cannabis use disorder, which often share common neural characteristics with other substance use disorders, that could inform prevention and treatment strategies.