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Background: While English is only the native language of 7.3% of the world's population and less than 20% can speak the language, nearly 75% of all scientific publications are English. Aim: To describe how and why scientific contributions from the non-English-speaking world have been excluded from addiction literature, and put forward suggestions for making this literature more accessible to the non-English-speaking population. Methods: A working group of the International Society of Addiction Journal Editors (ISAJE) conducted an iterative review of issues related to scientific publishing from the non-English-speaking world. Findings: We discuss several issues stemming from the predominance of English in the scientific addiction literature, including historical drivers, why this matters, and proposed solutions, focusing on the increased availability of translation services. Conclusion: The addition of non-English-speaking authors, editorial team members, and journals will increase the value, impact, and transparency of research findings and increase the accountability and inclusivity of scientific publications.

The anterior insular cortex (AIC) and its interconnected brain regions have been associated with both addiction and decision-making under uncertainty. However, the causal interactions in this uncertainty-encoding neurocircuitry and how these neural dynamics impact relapse remain elusive. Here, we used model-based fMRI to measure choice uncertainty in a motor decision task in 61 individuals with cocaine use disorder (CUD) and 25 healthy controls. CUD participants were assessed before discharge from a residential treatment program and followed for up to 24 weeks. We found that choice uncertainty was tracked by the AIC, dorsal anterior cingulate cortex (dACC), and ventral striatum (VS), across participants. Stronger activations in these regions measured pre-discharge predicted longer abstinence after discharge in individuals with CUD. Dynamic causal modelling revealed an AIC-to-dACC directed connectivity modulated by uncertainty in controls, but a dACC-to-AIC connectivity in CUD participants. This reversal was mostly driven by early-relapsers (

BACKGROUND Individuals with alcohol use disorder (AUD) and those who have experienced traumas or chronic stress exhibit dysregulated hypothalamic-pituitary-adrenal (HPA) axis reactivity. Whether and how trauma and stress histories interact with AUD to affect HPA axis reactivity has not been assessed. METHODS In the present study, 26 healthy male controls and 70 abstinent men with AUD were administered a pharmacologic probe [ovine corticotropin-releasing hormone (oCRH)] and psychosocial stressor to assess HPA axis reactivity. Plasma adrenocorticotropin hormone (ACTH) and cortisol were assessed every 10-20 minutes. Hierarchical clustering of multiple measures of trauma and stress identified 3 distinct clusters: childhood adversity, lifetime trauma, and chronic stress. General linear model procedures were used to examine main effects of group (AUD/control) and interaction effects of the 3 clusters upon net-integrated ACTH and cortisol response. RESULTS We found that higher levels of childhood adversity, lifetime trauma, and chronic stress were each associated with blunted oCRH-induced ACTH reactivity in controls, but not in the AUD group. Recent chronic stress within the prior 6 months had the strongest influence upon ACTH reactivity in the control group, and lifetime trauma, the least. CONCLUSIONS Childhood adversity, lifetime trauma, and chronic stress likely exert persistent, measurable effects upon HPA axis functioning in healthy controls. This association appears to be masked in individuals with AUD, potentially confounding studies examining the effects of stress, adversity, and/or trauma upon the HPA axis in this population during the protracted withdrawal phase of recovery. Future work targeting stress exposure and reactivity should consider the heightened effect of previous alcohol use relative to past adversity and trauma.

The use of psychoactive substances, including cannabis, has accompanied the development of civilization (1). (In the context of this paper, “psychoactive substances” refers specifically to substanc...

Relapse is one of the most perplexing problems of addiction. The dorsolateral prefrontal cortex is crucially involved in numerous cognitive and affective processes that are implicated in the phenotypes of both substance use disorders and other neuropsychiatric diseases and has become the principal site to deliver transcranial magnetic stimulation for their treatment. However, the dorsolateral prefrontal cortex is an anatomically large and functionally heterogeneous region, and the specific dorsolateral prefrontal cortex locus and dorsolateral prefrontal cortex-based functional circuits that contribute to drug relapse and/or treatment outcome remain unknown. We systematically investigated the relationship of cocaine relapse with functional circuits from 98 dorsolateral prefrontal cortex regions-of-interest defined by evenly sampling the entire surface of bilateral dorsolateral prefrontal cortex in a cohort of cocaine dependent patients (n = 43, 5 Fr) following a psychosocial treatment intervention. Cox regression models were utilized to predict relapse likelihood based on dorsolateral prefrontal cortex functional connectivity strength. Functional connectivity from only 3 of the 98 dorsolateral prefrontal cortex loci, one in the left and two in the right hemisphere, significantly predicted cocaine relapse with an accuracy of 83.9%, 84.6% and 85.4%, respectively. Combining all three loci significantly improved prediction validity to 87.5%. Protective and risk circuits related to these dorsolateral prefrontal cortex loci were identified that have previously been implicated to support ‘bottom up’ drive to use drug and ‘top down’ control over behaviour together with social emotional, learning and memory processing. Three dorsolateral prefrontal cortex-centric circuits were identified that predict relapse to cocaine use with high accuracy. These functionally distinct dorsolateral prefrontal cortex-based circuits provide insights into the multiple roles played by the dorsolateral prefrontal cortex in cognitive and affective functioning that affects treatment outcome. The identified dorsolateral prefrontal cortex loci may serve as potential neuromodulation targets to be tested in subsequent clinical studies for addiction treatment and as clinically relevant biomarkers of its efficacy. Zhai et al. identify three dorsolateral prefrontal cortex (dlPFC)-centric circuits that predict cocaine relapse with high accuracy, providing insights into the multiple roles of the dlPFC in brain functioning that affects treatment outcome and suggesting the dlPFC loci as potential neuromodulation targets for addiction treatment., Graphical Abstract Graphical Abstract

Aims The objective of this study is to address equivocation in estimates of selective serotonin reuptake inhibitor initiation (SSRI) effect on all-cause and alcohol-related ER visits, and medical or psychiatric admissions within 2 years of initial Post-Traumatic Stress Disorder (PTSD) diagnosis in patients with PTSD and Alcohol Use Disorder (AUD). Methods This study is a quasi-experimental, new-user-design cohort study of 3235 patients seen at the VA North Texas Healthcare System between January 1, 2000 and December 31, 2016. High dimensional propensity score (HDPS) techniques were used to estimate likelihood of SSRI initiation within 30 days of first PTSD diagnosis. Propensity scores were used to calculate weights for likelihood of SSRI initiation which were used to control for baseline covariates in estimations of SSRI medication effect on odds of each outcome occurring. Results Compared to those who did not receive SSRIs, patients prescribed an SSRI within 30 days showed significantly lower odds of alcohol-related ER visits (OR=0.668, 95%CI = 0.476 to 0.938, P = 0.02) and alcohol-related medical admissions (OR=0.583, 95%CI = 0.399 to 0.851, P = 0.005). Limitations Inconsistent assessment of PTSD severity necessitated the use of HDPS models to control for baseline confounding. Our study design mimicked intent-to-treat trial design and therefore could not control for SSRI initiations after the 30-day grace period following initial PTSD diagnosis. Conclusions SSRI initiation in patients with AUD and PTSD is associated with significantly reduced odds of alcohol-related medical hospitalization and alcohol-related ER visits within 2 years of first PTSD diagnosis. Additional studies are needed to verify these results.

Static functional connectivity (FC) analyses based on functional magnetic resonance imaging (fMRI) data have been extensively explored for studying various psychiatric conditions in the brain, including cocaine addiction. A recently emerging, more powerful technique, dynamic functional connectivity (DFC), studies how the FC dynamics change during the course of the fMRI experiments. The aim in this paper was to develop a computational approach, using a machine learning framework, to determine if DFC features were more successful than FC features in the classification of cocaine-dependent patients and healthy controls. fMRI data were obtained from of 25 healthy and 58 cocaine-dependent participants while performing a motor response inhibition task, stop signal task (SST). Group independent component analysis (ICA) was carried out on all participant data to compute spatially independent components (ICs). Eight ICs were selected manually as relevant brain networks, which were used to classify healthy vs. cocaine-dependent participants. FC and DFC measures of the chosen IC-pairs were used as features for the classification algorithm. Support Vector Machines were used for both feature selection/reduction and participant classification. Based on DFC with only seven IC pairs, participants were successfully classified with 95% accuracy (and with 90% accuracy with three IC pairs); whereas static FC yielded only 81% accuracy. Visual, sensorimotor, default-mode, and executive-control networks, amygdala and insula played the most significant role in the DFC-based classification. These findings support the use of DFC-based classification of fMRI data as a potential biomarker for the identification of cocaine dependence.

Background Treatment-seeking men with alcohol use disorder (AUD) classically exhibit a blunted hypothalamic-pituitary-adrenal (HPA) axis response to pharmacologic and behavioral provocations during the early phases of abstinence from alcohol. Independent of alcohol, a significant muting of HPA axis reactivity is also observed among racial minority (e.g. Black) individuals. The effect of AUD upon the altered HPA axis response of racial minority individuals has not been explored. The current work represents a secondary analysis of race and AUD status among a sample of men. Methods Healthy male controls (17 White, 7 Black) and four-to six-week abstinent men with AUD (49 White, 13 Black) were administered a psychosocial stressor and two pharmacologic probes [ovine corticotropin releasing hormone (oCRH) and cosyntropin] to assess HPA axis reactivity. Plasma cortisol and adrenocorticotropin hormone (ACTH) were assessed at 10–20 min intervals prior to and following behavioral and pharmacological stimulation. Basal and net-integrated responses following provocations were analyzed to identify potential group differences. A measure of childhood adversity was also obtained to consider the implications of prior stressors upon HPA axis function. Results A three-fold increase in oCRH-induced ACTH was seen in Black men relative to White men regardless of AUD status. Adversity exerted a dampening effect on this pituitary sensitivity within Black controls only. Adjusted for adversity, a significant blunting effect of AUD status on ACTH reactivity was identified within White participants following oCRH. No group differences were present following cosyntropin administration. In response to the psychosocial stressor, White, but not Black, men with AUD experienced the expected blunting of cortisol reactivity relative to White controls. Rather, Black men with AUD exhibited greater cortisol reactivity relative to White men with AUD. Conclusions Differences in HPA axis reactivity associated with race were present in men with and without AUD. Explanatory biological mechanisms of the relationship between alcohol use and/or stress, in both healthy and unhealthy populations, may require a reassessment in different racial populations.

Background: Bupropion is a substituted cathinone compound widely used as a first line or add-on treatment for depression, smoking cessation, and more recently in combination with naltrexone for weight loss. As abuse of synthetic cathinone compounds has received more attention in recent years, concern about the misuse potential of bupropion has grown as well. Objectives: We review bupropion pharmacology and assessments of misuse potential including preclinical evidence, human studies, and post-marketing surveillance of bupropion misuse. Methods: This review reports the results of a systematic review of publications evaluating the potential for bupropion to be misused. Publications were identified using PubMed and Medline through Ovid® as well as iterative bibliographic searches. A summary of data from informal sources of information including substance-user experience from online forum entries is included. Results: Preclinical evidence demonstrates some potential for misuse based on psychomotor, discrimination, self-administration, and conditioned place preference tasks. However, this potential is less than that of commonly misused stimulants. Studies in human populations similarly indicate that bupropion shares interoceptive effects with other stimulants, but lacks some key reinforcing effects of other stimulants. In the real-world setting, misuse of bupropion occurs, but is uncommon. Adverse effects of bupropion misuse are frequently cited as significant barriers to obtaining any desired interoceptive effect. Conclusions: While bupropion demonstrates some potential for misuse, pharmacological differences from other structurally-related stimulants limit bupropion's reinforcing effects. Without additional data indicating susceptibility of specific populations to bupropion misuse, there is no empirical data suggesting a need to modify bupropion prescribing patterns.

BackgroundRelapse is one of the most perplexing problems of addiction. The dorsolateral prefrontal cortex (DLPFC) is crucially involved in numerous cognitive and affective processes that are implicated in phenotypes of addiction, and is one of the most frequently reported brain regions with aberrant functionality in substance use disorders. However, the DLPFC is an anatomically large and functionally heterogeneous region, and the specific DLPFC-based circuits that contribute to drug relapse remain unknown.MethodsWe systematically investigated the relationship of cocaine relapse with 98 DLPFC functional circuits defined by evenly sampling the entire bilateral DLPFC in a cohort of cocaine dependent patients (n=43, 5F) following a psychosocial treatment intervention. A Cox regression model was utilized to predict relapse likelihood based on DLPFC functional connectivity strength.ResultsFunctional connectivity from 3 of the 98 DLPFC loci, one on the left and two on the right hemisphere, significantly predicted cocaine relapse with an accuracy of 83.9%, 84.7% and 85.4%, respectively. Combining all three significantly improved prediction validity to 87.5%. Protective and risk circuits related to these DLPFC loci were identified that are known to support “bottom up” drive to use drug and “top down” control over behavior together with social emotional, learning and memory processing.ConclusionThree DLPFC-centric circuits were identified that predict relapse to cocaine use with high accuracy. These functionally distinct DLPFC-based circuits provide insights into the multiple roles played by the DLPFC in cognitive and affective functioning that affects treatment outcome. The identified DLPFC loci may serve as potential neuromodulation targets for addiction treatment and as clinically relevant biomarkers of its efficacy.

Importance The American Medical Association has acknowledged the public health threat posed by racism in medicine. While clinicians in psychiatry have echoed the sentiment, the research community has largely been silent. Current understanding of the biological domains that underlie psychiatric disorders was historically established by studying White populations, often leaving widely used treatments ineffective for Asian, Black, Hispanic, Indigenous, and other racial and ethnic minority individuals. This article addresses how undersampling of racial and ethnic minority individuals has led to overgeneralized physiological findings, the implications for development of psychiatric treatments, and steps to improve service to racially diverse communities. Observations Three primary observations regarding differences associated with race and ethnicity have been addressed in the existing psychiatric research: misdiagnosis, medication nonadherence, and treatment efficacy and expression of adverse effects. While cultural factors have been discussed as potential factors associated with these differences, a lack of understanding of physiologic systems may be foundational to each of these issues. Recent evidence points to race differences in psychophysiological measures, likely attributed to factors including the lived experience of racism as opposed to inherent biological differences. This mounting evidence supports a reassessment of existing work to examine potential divergent patterns within racial and ethnic groups. The following strategies may improve understanding of the influence of racism on physiology, allowing clinicians to better address psychiatric symptoms and improve existing treatment approaches. Thus, psychiatric researchers need to (1) understand the historic and current terminology forraceandethnicityand use appropriate terms and categories as defined by sociologists, population health experts, and databases while respecting individuals’ right to self-identify, (2) refine research questions, and (3) reexamine research data to determine whether patterns observed in largely White populations can extend to other groups. To appropriately implement these steps, researchers must accept the discomfort that accompanies growth, invite scientists from diverse backgrounds to participate, and use resources to increase diversity in recruitment of study participants. This will require a commitment from funding agencies to provide adequate support to recruit and investigate large, diverse samples. Conclusions and Relevance To create more suitable medical treatments and improve the quality of care received by those with psychiatric conditions, further discussion is needed surrounding the physiologic toll that racism has had on multiple generations of racial and ethnic minority groups and how that may alter responsivity to biobehavioral interventions. To better inform psychiatric research, the resources provided must be expanded, basic physiologic studies should be replicated with more diverse samples and adequate analyses, and psychiatry scientists must reconsider approaches to clinical research.

Emergent studies suggest a bidirectional relationship between brain functioning and the skin. This neurocutaneous connection may be responsible for the reward response to tanning and, thus, may contribute to excessive tanning behavior. To date, however, this association has not yet been examined.To explore whether intrinsic brain functional connectivity within the default mode network (DMN) is related to indoor tanning behavior.Resting state functional connectivity (rsFC) was obtained in twenty adults (16 females) with a history of indoor tanning. Using a seed-based [(posterior cingulate cortex (PCC)] approach, the relationship between tanning severity and FC strength was assessed. Tanning severity was measured with symptom count from the Structured Clinical Interview for Tanning Abuse and Dependence (SITAD) and tanning intensity (lifetime indoor tanning episodes/years tanning).rsFC strength between the PCC and other DMN regions (left globus pallidus, left medial frontal gyrus, left superior frontal gyrus) is positively correlated with tanning symptom count. rsFC strength between the PCC and salience network regions (right anterior cingulate cortex, left inferior parietal lobe, left inferior temporal gyrus) is correlated with tanning intensity.Greater connectivity between tanning severity and DMN and salience network connectivity suggests that heightened self-awareness of salient stimuli may be a mechanism that underlies frequent tanning behavior. These findings add to the growing evidence of brain-skin connection and reflect dysregulation in the reward processing networks in those with frequent tanning.

BACKGROUND AND AIMS Non-medical use of prescribed stimulant medications is a growing concern. This study's aims were to ascertain the demographics of stimulant medication users compared with non-users, examine temporal trends of stimulant medication use and estimate risk factors for development of amphetamine use disorder (AUD) and mortality among new users of stimulant medications. DESIGN Cox proportional hazards regression in a retrospective cohort adjusted by baseline covariates. SETTING United States, national administrative database of the Veterans Affairs (VA) health-care system. PARTICIPANTS Adult incident users of stimulant medications (n = 78 829) from fiscal years (FY) 2001 to 2012. MEASUREMENTS Primary outcomes were time-to-event: (1) occurrence of AUD diagnosis and (2) death. Baseline covariates included demographic information, Food and Drug Administration (FDA)-approved indications for stimulant use, substance use disorders (SUD) and depression. FINDINGS Stimulant users compared with non-users were younger, more likely to be non-Hispanic white and female. Incident stimulant medication users increased threefold from FY2001-FY2012 and eightfold among adults aged 18-44 years. Nearly one in 10 incident users in FY2012 had a comorbid baseline SUD. Off-label use was common-nearly three of every five incident users in FY2012. Comorbid SUDs among incident stimulant medication users were risk factors for occurrence of AUD during follow-up, with adjusted hazard ratio (AHR) estimates ranging from 1.54 to 2.83 (Ps

Previous reviews have examined the use of theoretically supported combinations of drugs for the treatment of alcohol use disorder. This review seeks to examine the strengths and limitations of current clinical evidence for the use of combined pharmacological interventions intended to treat alcohol use disorder.The objective of this review was to identify combinations of pharmacological treatments for alcohol use disorder, and assess the strength of clinical evidence for these treatments.We conducted searches using PubMed, EMBASENine hundred and eighty-four publications were initially screened for inclusion after duplicates were removed. The search identified 16 publications evaluating drug combinations for the treatment of alcohol use disorder. The majority of published trials included naltrexone combined with one of the following: gabapentin, ondansetron, acamprosate, gamma-hydroxybutyrate, sertraline, quetiapine, or escitalopram plus gamma-hydroxybutyrate. Other combinations included 5-hydroxytryptophan with carbidopa/levodopa, gamma-hydroxybutyrate with disulfiram, acamprosate with disulfiram, and mirtazapine with quetiapine. Interpretation of results across studies was limited by low statistical power, and heterogeneity of drug combinations and outcome measures. Drug combination effect sizes were comparable to those observed in single-agent trials.No significant benefit for the use of combinations over single agents was observed. However, benefit may be observed when combined pharmacological interventions address specific symptoms of alcohol use disorder known to be influenced by combination components, or when combinations are used in specific subpopulations in which combination components demonstrate benefit.

The gap between treatment utilization and treatment need for substance use disorders (SUDs) remains a significant concern in our field. While the growing call to bridge this gap often takes the form of more treatment services and/or better integration of existing services, this perspective proposes that more effective labels for and transparent descriptions of existing services would also have a meaningful impact. Adopting the perspective of a consumer-based health-care model (wherein treatments and services are products and patients are consumers) allows us to consider how labels like Addiction-focused Medical Management, Medication-Assisted Treatment, Medication-Assisted Therapy, and others may actually be contributing to the underutilization problem rather than alleviating it. In this perspective, "Medication-Assisted Therapy" for opioid-use disorder (OUD) is singled out and discussed as inherently confusing, providing the message that pharmacotherapy for this disorder is a secondary treatment to other services which are generally regarded, in practice, as ancillary. That this mixed message is occurring amidst a nationwide "opioid epidemic" is a potential cause for concern and may actually serve to reinforce the longstanding, documented stigma against OUD pharmacotherapy. We recommend that referring to pharmacotherapy for SUD as simply "medication," as we do for other chronic medical disorders, will bring both clarity and precision to this effective treatment approach.

It is reasonable to consider family discord after treatment as a potential target for a next-step intervention, since family discord is often comorbid with substance use disorders.This study evaluated family discord after completing an initial course of treatment as a predictor of substance use and retention in the community treatment program during follow-up.Patients were from two multisite randomized clinical trials implemented through the Clinical Trials Network of the National Institute on Drug Abuse. There were 315 participants from Study 1 (12-week posttreatment follow-up) and 295 participants from Study 2 (8-week posttreatment follow-up). Negative binomial and logistic regression were used to estimate days of substance use and odds of retention in the community treatment program at follow-up, respectively, from family discord status.Family discord was significantly associated with more days of substance use during the posttreatment follow-up period than those without family discord in both Study 1 (9.12 vs. 2.89 days, p =.0001) and Study 2 (5.58 vs. 2.83 days, p =.0062). Family discord was significantly associated with lower retention in the community treatment program at follow-up than those not reporting family discord in Study 1 (47.6% vs. 60.6%; p =.03), but not in Study 2 (55.3% vs. 64.9%; p =.11).Family discord after an initial course of treatment might be a clinically relevant predictor of substance use. There is mixed support for a conclusion that family discord is associated with lower retention in the community treatment program at follow-up.

Background: The legalization of cannabis for adult use is being increasingly embraced in several countries and local entities. A driving force for these changes has been the individual, family, community, societal, and economic costs of cannabis prohibition, which have fallen most heavily upon disadvantaged minority populations.Objectives: In this review, we explore whether the legalization of cannabis has begun to correct the injustices of cannabis prohibition. Progress is assessed in five areas of social justice related to cannabis prohibition: expungement of previous arrests and convictions for cannabis-related crimes that are no longer illegal; consequences of cannabis-related offenses in a cannabis-legal environment; diversity of the cannabis-legal industry; funding of equity and/or restorative justice programs for those communities most affected by cannabis prohibition; and risks of cannabis legalization negatively impacting the populations that most suffered under the legacy of cannabis prohibition.Methods: Iterative and focused review.Results: There has been some progress in expunging previous cannabis-related convictions, particularly misdemeanors, and decreasing cannabis-related arrests. Encouraging diversity in the cannabis industry and the funding of equity programs has been very limited. There is no evidence to-date that populations that have suffered most as a result of cannabis prohibition are at increased risk from its legalization.Conclusions: Focused regulatory efforts and financial resources (from both cannabis revenue and savings from the abolition of cannabis prohibition) as well as more attentive data collection and analysis should be utilized to assure that all individuals experience the benefits, and avoid the consequences, of cannabis legalization.

Cocaine addiction is characterized by notoriously high relapse rates following treatment. Recent efforts to address poor treatment outcomes have turned to potential neural markers of relapse risk. Accordingly, the present study examined resting state functional connectivity (rsFC) within and between three large-scale cortical networks: the default mode network (DMN), salience network (SN) and executive control network (ECN). All three have been implicated in relapse-related phenomena including craving, withdrawal and executive control deficits. Forty-five cocaine-dependent individuals and 22 healthy controls completed 6-min resting fMRI scans, The Wisconsin Card Sorting Task, Continuous Performance Test and Cocaine Craving Questionnaire. Cocaine-dependent individuals completed all measures in the final week of a residential treatment episode. Ten control and 9 abstinent cocaine-dependent individuals returned for 3-6 month follow-up scan visits. A group-level independent component analysis was employed to generate ECN, DMN and SN components. For individuals abstinent up to day 30 post-treatment (n = 21), we found enhanced pre-discharge rsFC between the left ECN and both the right ECN and SN as well as between the right ECN and left ECN. Left ECN rsFC effects remained elevated 3-6 months later among abstinent cocaine-dependent individuals. Relapse was related to fewer years of education and more years smoking but no other demographic, clinical, treatment and neurocognitive characteristics. Findings suggest that interhemispheric ECN and ECN-SN connectivity strength may protect against relapse to cocaine use following treatment. These patterns of enhanced interhemispheric network connectivity may reflect a greater capacity to engage executive control processes when faced with opportunities to use cocaine post-treatment.

Since the late 1980s, opioid-related morbidity and mortality in the United States has dramatically increased. This serious epidemic requires a coordinated medical, public policy, and social response. It is becoming readily apparent that widespread provision of naloxone may help to address this problem. However, because naloxone access laws vary between states, the extent of antidote dissemination may be limited by a given provider's geographic location.This review targets a physician or prescriber audience, in hopes of providing evidence for the safety and utility of naloxone, education on the baseline legal liability of naloxone provision and protections afforded by access laws, and resources for the proposal of statewide legislation to promote antidote distribution.Evidence suggests that naloxone administration by laypersons, pursuant to physician prescription or standing order, is safe and effective for reversal of opioid overdose. As of July 2015, 44 states and the District of Columbia have passed naloxone access laws, offering varying degrees of protections for prescribers. Although the likelihood of naloxone-related legal action may parallel that inherent to the usual practice of medicine, providers should be mindful of potential scenarios, exercise methods to mitigate risk, and appreciate the utility of comprehensive naloxone access legislation in orchestrating a coordinated response to the opioid overdose epidemic.

Background: Decision-making processes have been posited to affect treatment outcome in addicted patients. Objective: The present multi-site study assessed whether two measures of decision-making predicted relapse and subsequent use in stimulant-dependent patients. Methods: A total of 160 methamphetamine- or cocaine-dependent patients participating in a multi-site clinical trial evaluating a modified 12-step facilitation intervention for stimulant-dependent patients (STAGE-12) were assessed. Decision-making processes of risk and delay (Iowa Gambling Task [IGT]) and response reversal (Wisconsin Card Sorting Task [WCST]) were obtained shortly after treatment admission followed by assessment of stimulant use over the next six months. The relationships of the IGT and WCST (Perseverative Errors) with relapse (yes/no) and days of stimulant use during the 6-month period following post-randomization were evaluated. Results: Performance on the IGT and WCST did not significantly predict relapse status or time to relapse. Unexpectedly, worse performance on the IGT was associated with a fewer number of stimulant use days (p = 0.001). In contrast, worse performance on the WCST (more perseverative errors) was associated with a greater number of stimulant use days (p = 0.0003). The predictive effects of perseverative errors on subsequent use were confined to methamphetamine-dependent and Minority participants. Conclusions: Decision-making processes, as measured in the current study, do not uniformly predict relapse or subsequent use. A decrease in the salience attribution of non-drug reinforcers may explain the positive relationship between IGT performance and post-relapse use. More comprehensive and global measures of impulsiveness may better assess relapse risk and use.

Rational Cue-induced craving memories, linked to drug-seeking behaviors, require key molecular processes for memory reconsolidation. Lidocaine, a sodium channel blocker, inhibits NMDA receptor activation and suppresses nitric oxide and ERK production. These processes are required for memory re-consolidation; inhibiting them may reduce cue-related craving memories in cocaine dependent subjects. Objectives To assess the efficacy of lidocaine in decreasing cue-induced cocaine craving and cocaine use. Methods Treatment-seeking cocaine-dependent participants (n = 33, 25 men) were recruited. Personalized craving and relaxation scripts were developed. Participants were then randomly assigned in a double-blind design to either receive intravenous lidocaine immediately following a cocaine craving script (lidocaine/craving), saline following a craving script (saline/craving), or lidocaine following a relaxation script (lidocaine/relax). One week following the infusion, cue-induced craving was assessed in the same paradigm without an infusion. Cocaine use and craving were assessed for 4 weeks following infusion. Results The administration of lidocaine during craving induction (lidocaine/craving) did not decrease cue-induced craving during craving reactivation one week later or craving and cocaine use over the 4-week follow-up period compared to the saline/craving group. There were no significant differences in craving and cocaine use between the lidocaine/relax and saline/craving groups. Conclusion Lidocaine administered following craving induction did not decrease subsequent cue-induced craving or cocaine use. Blocking the reconsolidation of craving-related memories with pharmacological agents remains an important area of investigation.

Highlights • Individuals with alcohol use disorder were randomized to prazosin or placebo. • Greater deactivation in PCC and vmPFC to high-threat versus low-threat was observed. • Prazosin reduced subjective anxiety levels but did not change brain activity. • Patients with low anticipatory anxiety did not improve on prazosin. • Greater vmPFC deactivation predicted poor treatment response to prazosin., Background Higher levels of anxiety, negative affect, and impaired emotion regulation are associated with alcohol use disorder (AUD) and contribute to relapse and worse treatment outcomes. Prazosin, while typically used to treat post-traumatic stress disorder (PTSD) and other anxiety disorders, has shown promise for treating AUD. In order to better understand these underlying neural processes in individuals with AUD, our aims in this study were to measure brain activation during an anticipatory anxiety task before treatment to determine whether observed patterns supported previous work. We then aimed to measure the effects of prazosin on patients with AUD and explore whether greater baseline anticipatory anxiety (as measured by subjective and neural measures) predicts better treatment outcomes. Methods Thirty-four individuals seeking treatment for AUD participated in a six-week placebo-controlled study of prazosin and underwent an anticipatory anxiety task during fMRI scans at baseline and three weeks. Alcohol use over six weeks was measured. Results Greater levels of subjective anxiety and deactivation in posterior cingulate cortex (PCC) and ventromedial prefrontal cortex (vmPFC) were observed during high-threat stimuli compared to low-threat stimuli. Compared to placebo, prazosin reduced subjective anxiety to high-threat stimuli but there were no observed significant effects of prazosin on brain activation during the task. However, AUD patients with greater vmPFC deactivation during high threat relative to low threat and patients with low baseline anticipatory anxiety during the task had worse clinical outcomes on prazosin. Conclusions Deactivation in PCC and vmPFC to high-threat stimuli replicated previous work and shows promise for further study as a marker for AUD. Although prazosin did not affect brain activation in the regions of interest during the anticipatory anxiety task, subjective levels of anxiety and brain activation in vmPFC predicted treatment outcomes in individuals with AUD undergoing treatment with prazosin, highlighting individuals more likely to benefit from prazosin than others.

Aims The current study examined a large community cohort to understand relationships between indicators of alcohol consumption and hippocampal volume. Short summary Alcohol use measures were not associated with hippocampal volume in a population-based sample. However, alcohol consumption was associated with hippocampal volume reduction in subsets of the sample including subjects aged ≥50 years old, and those with none to moderate levels of depressive symptoms. Methods A total of 1848 adults with magnetic resonance imaging (MRI) and alcohol consumption data were included. Multiple linear regressions were performed with left or right hippocampal volume as dependent variables, and age, gender, race, education, body mass index, Quick Inventory of Depressive Symptomatology (QIDS-SR) scores, drinks per week (DPW), aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST/ALT, γ-glutamyl transferase and mean corpuscular volume (MCV) as independent variables. Post hoc analyses were conducted to assess interactions of demographic factors and variables of interest (DPW, AST, ALT, AST/ALT, GGT and MCV). For statistically significant interactions, analyses were conducted in groups split by gender, depression (QIDS-SR scores ≥11 and

Substance use disorders are characterized by a profound intersubject (phenotypic) variability in the expression of addictive symptomatology and propensity to relapse following treatment. However, laboratory investigations have primarily focused on common neural substrates in addiction, and have not yet been able to identify mechanisms that can account for the multifaceted phenotypic behaviors reported in literature. To investigate this knowledge gap theoretically, here we simulated phenotypic variations in addiction symptomology and responses to putative treatments, using both a neural model based on cortico-striatal circuit dynamics, and an algorithmic model of reinforcement learning. These simulations rely on the widely accepted assumption that both the ventral, model-based, goal-directed system and the dorsal, model-free, habitual system are vulnerable to extra-physiologic dopamine reinforcements triggered by drug consumption. We found that endophenotypic differences in the balance between the two circuit or control systems resulted in an inverted U-shape in optimal choice behavior. Specifically, greater unbalance led to a higher likelihood of developing addiction and more severe drug-taking behaviors. Furthermore, endophenotypes with opposite asymmetrical biases among cortico-striatal circuits expressed similar addiction behaviors, but responded differently to simulated treatments, suggesting personalized treatment development could rely on endophenotypic rather than phenotypic differentiations. We propose our simulated results, confirmed across neural and algorithmic levels of analysis, inform on a fundamental and, to date, neglected quantitative method to characterize clinical heterogeneity in addiction.

Traditional approaches to subgroup analyses that test each moderating factor as a separate hypothesis can lead to erroneous conclusions due to the problems of multiple comparisons, model misspecification, and multicollinearity.To demonstrate a novel, systematic approach to subgroup analyses that avoids these pitfalls.A Best Approximating Model (BAM) approach that identifies multiple moderators and estimates their simultaneous impact on treatment effect sizes was applied to a randomized, controlled, 11-week, double-blind efficacy trial on smoking cessation of adult smokers with attention-deficit/hyperactivity disorder (ADHD), randomized to either OROS-methylphenidate (n = 127) or placebo (n = 128), and treated with nicotine patch. Binary outcomes measures were prolonged smoking abstinence and point prevalence smoking abstinence.Although the original clinical trial data analysis showed no treatment effect on smoking cessation, the BAM analysis showed significant subgroup effects for the primary outcome of prolonged smoking abstinence: (1) lifetime history of substance use disorders (adjusted odds ratio [AOR] 0.27; 95% confidence interval [CI] 0.10-0.74), and (2) more severe ADHD symptoms (baseline score36; AOR 2.64; 95% CI 1.17-5.96). A significant subgroup effect was also shown for the secondary outcome of point prevalence smoking abstinence--age 18 to 29 years (AOR 0.23; 95% CI 0.07-0.76).The BAM analysis resulted in different conclusions about subgroup effects compared to a hypothesis-driven approach. By examining moderator independence and avoiding multiple testing, BAMs have the potential to better identify and explain how treatment effects vary across subgroups in heterogeneous patient populations, thus providing better guidance to more effectively match individual patients with specific treatments.

Methanol-related toxic effects from alcohol, including thousands of deaths, were but a few of the many unplanned consequences of alcohol prohibition in the United States (1920–1933). For at least t...

Bipolar disorder (BD) spectrum and alcohol use disorders (AUDs) commonly occur together. Comorbidity between the two conditions predisposes patients to elevated risks of adverse outcomes, including hospitalization and suicide, compared with either condition alone. Despite the consistent relationship observed between BD and AUD, the underlying cause remains incompletely characterized. Few trials conducted have been able to identify promising interventions for patients with these disease states. The antipsychotic quetiapine has been evaluated most commonly as a therapeutic agent for patients with BD and AUD followed by naltrexone and acamprosate. Randomized controlled trials of quetiapine have consistently reported a lack of efficacy for the treatment of patients with BD and AUD. Trials of acamprosate have also been negative but small in size. Results of the sole randomized controlled trial of naltrexone have found large treatment effect sizes, but no statistically significant difference between treatment groups. Other agents including the antipsychotic aripiprazole, mood stabilizing agents including lamotrigine, lithium, and divalproex, and the antiepileptic agent topiramate have also been evaluated for the treatment of BD and AUD with mixed findings. The lone statistically significant treatment effect was observed in a randomized, placebo-controlled trial of divalproex added on to lithium which demonstrated a reduction in alcohol use. This review summarizes the available clinical evidence and current guideline recommendations for the treatment of comorbid BD and AUD, and provides discussion and recommendations based on the current literature.

Opioid abuse is a national epidemic in the United States, where it is estimated that a prescription drug overdose death occurs every 19 minutes. While opioids are highly effective in acute and subacute pain control, their use for treatment of chronic pain is controversial. Chronic opioids use is associated with tolerance, dependency, hyperalgesia. Although there are new strategies and practice guidelines to reduce opioid dependence and opioid prescription drug overdose, there has been little focus on development of opioid-sparing therapeutic approaches. Lidocaine infusion has been shown to be successful in controlling pain where other agents have failed. The opioid sparing properties of lidocaine infusion added to its analgesic and antihyperalgesic properties make lidocaine infusion a viable option for pain control in opioid dependent patients. In this review, we provide an overview of the opioid abuse epidemic, and we outline current evidence supporting the potential use of lidocaine infusion as an adjuvant therapeutic approach for management of chronic pain.

Clinical and cultural characteristics of Hispanic adolescent heroin users are not well described. The current exploratory study was conducted to describe a sample of in-treatment Hispanic adolescents with opioid dependence, specifically, cheese heroin. Mexican and Mexican American adolescents with heroin dependence (N = 72) in three treatment programs were interviewed and completed self-report measures. Participants reported, on average, first using cheese heroin at age 13.5 years and daily use at age 14.2 years. The majority (74%) reported a previous overdose. Adolescents being raised by caregivers other than both biological parents, who used drugs with relatives, and whose immediate family members have documentation to be in the United States fared worse on several indicators of drug use severity and other risky behaviors. The self-reported brief time period from first use to daily use strongly suggests the need for early prevention efforts. Additional research is needed to add to these preliminary results and inform prevention efforts.

Long-term cocaine use is known to negatively impact neural and cerebrovascular systems. However, the use of imaging markers to separately assess these parameters remains challenging. The primary reason is that most functional imaging markers, such as cerebral blood flow, functional connectivity, and task-evoked functional MRI, are known to reflect a complex interplay between neural and vascular components, thus the interpretation of the results is not straightforward. The goal of the present study is to examine neural-activity-specific changes in cocaine addiction, using cerebral metabolic rate of oxygen (CMRO2) as a surrogate marker of aggregated neural activity. We applied a recently developed CMRO2 technique in 13 cocaine-addicted subjects and 13 age- and gender-matched control subjects, and examined the impact of long-term cocaine use on CMRO2. Our results showed that CMRO2 in cocaine-addicted subjects (152 ± 16 µmol/100 g/min) is significantly lower (p = 0.031) than that in controls (169 ± 20 µmol/100 g/min). Furthermore, the severity of this decreased metabolism is associated with lifetime cocaine use (p = 0.05). Additionally, the CMRO2 reduction was accompanied by a trend of decrease in cerebral blood flow (p = 0.058), but venous oxygenation was unaffected (p = 0.96), which suggested that the CMRO2 change may be attributed to a vascular deficiency in chronic cocaine users. To our knowledge, this is the first study to measure CMRO2 in cocaine-addicted individuals. Our findings suggest that CMRO2 may be a promising approach for assessing the long-term effects of cocaine use on the brain.

Stress response biologic systems are altered in alcohol-dependent individuals. Early life stress (ELS) is associated with a heightened risk of alcohol dependence, presumably because of stress-induced neuroplastic changes. This study was designed to assess the contribution of ELS to a stress-induced neural response in alcohol-dependent participants. Fifteen alcohol-dependent men abstinent for 3-5 weeks and 15 age- and race-matched healthy controls were studied. Anticipatory anxiety was induced by a conditioned stimulus paired with an uncertain physically painful unconditioned stressor. Neural response was assessed with functional magnetic resonance imaging. ELS was assessed with the Childhood Adversity Interview. There was a significant interaction between ELS and group on blood-oxygen-level-dependent (BOLD) amplitude during anticipatory anxiety in the right amygdala and bilateral orbitofrontal cortex, posterior putamen and insula. Higher ELS scores were associated with decreased BOLD amplitude during anticipatory anxiety in alcohol-dependent, but not control, participants. These findings suggest that ELS interacts with alcohol dependence to induce a muted cortico-striatal response to high threat stimuli. Allostatic changes due to both ELS and excessive alcohol use may jointly induce persistent changes in the neural response to acute stressors.

Allostatic load from both environmental stressors and persistent glucocorticoid secretion has been associated with disease severity in alcohol dependence. Heightened relapse risk and/or drinking severity, in particular, may be a reaction to alcohol- and withdrawal-induced changes in physiological stress response systems coupled with ongoing life stress, although their shared contributions upon drinking severity have not been assessed. To investigate the combined contribution of hypothalamic-pituitary-adrenal (HPA) reactivity and environmental stressors (e.g., ongoing life stress) to relapse severity in alcohol-dependent men following treatment, plasma adrenocorticotropin (ACTH) and cortisol were obtained in 4-6 weeks abstinent alcohol-dependent men (n=41) following a psychosocial stressor [the Trier Social Stress Test (TSST)] and two pharmacological provocations [ovine corticotropin releasing factor (oCRH) and cosyntropin]. Following treatment discharge, drinking outcomes (primary outcome: drinks per drinking day (DDD); secondary outcomes: total drinks and drinking days) were assessed weekly and ongoing life stress was assessed biweekly for 24 weeks following treatment discharge. Generalized estimating equation models of drinking severity were fit with basal and stimulated ACTH and cortisol concentrations as predictors and ongoing life stress as the moderator. Greater levels of life stress were independently associated with greater drinking intensity (DDD and total drinks) but not frequency (days drinking). Higher basal cortisol:ACTH or provoked cortisol:ACTH ratios were strongly associated with greater post-treatment DDD in individuals who experienced higher levels of ongoing stress. In conclusion, ongoing life stress is associated with post-treatment drinking intensity in alcohol dependent men; stress also strengthens the relationship between adrenocortical sensitivity and post-treatment drinking. Physiological measures of allostatic load and environmental stressors conjointly increase relapse intensity.

Research suggests that mentholated cigarettes may play a role in cocaine dependence. The purpose of the present study was to expand upon the research on mentholated cigarettes and cocaine dependence and to evaluate the role of mentholated cigarettes in methamphetamine dependence.Secondary analysis of a multisite, randomized trial evaluating the impact of smoking-cessation treatment in stimulant-dependent outpatients (N=538). Participants' reasons for concurrent use of cigarettes and illicit stimulants were assessed via self-report. Stimulant-abstinence was measured by self-report and urine drug screens. Smoking cessation was assessed via self-report and carbon monoxide levels.Of the 301 cocaine-dependent participants, 201 (67%) were menthol and 100 (33%) were non-menthol cigarette smokers. Cocaine-dependent participants who smoked menthol, compared to non-menthol, cigarettes were significantly more likely to report that cigarettes prolong their cocaine high (X(2)(1)=16.3, p.0001, OR=3.58 [95% CI: 1.88-6.79]) and were less likely to be stimulant abstinent during active treatment (W=3.6, p0.001, d=.39 [95% CI: 0.16-0.62]), at 3-month follow-up (X(2)(1)=14.4, p0.001, OR=.32 [95% CI: 0.17-0.58]), and at 6-month follow-up (X(2)(1)=4.6, p=0.03, OR=.53 [95% CI: 0.29-0.95]). No parallel differences were found between menthol and non-menthol methamphetamine-dependent smokers. The prevalence of Caucasian menthol smokers was significantly greater in the cocaine-dependent participants (37.2%) than in the methamphetamine-dependent participants (17.61%), (X(2)(1)=14.4, p.001, OR=2.77 [95% CI:1.62-4.73]). Smoking cessation was not significantly associated with cigarette type for either cocaine- or methamphetamine-dependent participants.The present results suggest that mentholated cigarettes play a role in cocaine, but not methamphetamine, dependence.

Research on the relationship of alcohol and disasters has yielded mixed conclusions. Some studies investigate alcohol consumption but others examine alcohol use disorders in relation to disaster. Alcohol consumption and alcohol use disorders have not be studied concurrently in relation to specific disaster trauma exposures. A volunteer sample of 379 individuals from New York City agencies affected by the September 11, 2001 (9/11) attacks on World Trade Center were assessed approximately 3 years postdisaster for alcohol consumption and alcohol use disorders relative to specific disaster exposures. Increases in alcohol consumption were relatively small, eventually returning to pre-9/11 levels, with few cases of new alcohol use disorders or alcohol relapse. The findings suggest that postdisaster alcohol use has negligible clinical relevance for most of the population. Scarce disaster resources should be focused on those at identified risk of excessive alcohol use, that is, those with pre-existing alcohol or other psychiatric disorders.

Current treatments for addiction are frequently ineffective. Hallucinogenic therapy has been indicated as helpful for a range of substance use disorders, yet this approach remains understudied and publicly unavailable. It is nonetheless a promising treatment, which has significant, long-term beneficial effects with single doses and a profile characterized by general safety, low toxicity, and non-addictiveness. However, pharmacological interventions, such as hallucinogens, should not be offered if the same effects (e.g. psychological insights/mystical experiences) and outcomes (e.g. decreased drug use) could be achieved absent pharmacological intervention. To date, there have been no clinical comparisons of drug-induced altered states with non-drug-induced states for addiction treatment. We propose and then outline a clinical trial to address this gap in knowledge. The proposed design would evaluate abstinence outcomes in a population of prescription opioid abusers after exposure to one of three conditions: a drug-induced altered state using psilocybin, a non-drug-induced altered state via hyperventilation (Holotropic Breathwork), and an active placebo with niacin. The outcomes of such a study would reveal important differences in therapeutic potential by discriminating hallucinogen-dependent effects from those psychological effects resulting from altered states.