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A recent study demonstrated that during a single sampling period, 0.1 mg of intravenous (IV) nicotine (vs. placebo) was found to be the threshold for subjective and physiological drug effects. The present study is a secondary analysis evaluating whether the threshold for subjective and physiological effects is similar when the subject has repeated opportunities to choose blinded doses of nicotine versus placebo. We also examined whether cigarette craving, withdrawal, and rate of nicotine metabolism affected nicotine reinforcement, defined by a greater number of nicotine choices than placebo. Young adult (

Cocaine use disorder (CUD) is a devastating disorder, impacting both individuals and society. Individuals with CUD face many barriers in accessing treatment for CUD, and most individuals with CUD never receive treatment. In this review, we provide an overview of CUD, including risk factors for CUD, common co-occurring disorders, acute and chronic effects of cocaine use, and currently available pharmacological and behavioral treatments. There are no FDA-approved pharmacological treatments for CUD. Future studies with larger sample sizes and testing treatment combinations are warranted. However, individuals with CUD and co-occurring disorders (eg, a mood or anxiety disorder) may benefit from medication treatments. There are behavioral interventions that have demonstrated efficacy in treating CUD - contingency management (CM) and cognitive-behavioral therapy for substance use disorders (CBT-SUD) in particular - however many barriers remain in delivering these treatments to patients. Following the discussion of current treatments, we highlight some promising emerging treatments, as well as offer a framework that can be used in building a treatment plan for individuals with CUD.

To address the ongoing opioid epidemic, there has been an increased focus on the treatment and evaluation of opioid use disorder (OUD). OUD and chronic pain (CP) frequently co-occur; however, little is known about the additional comorbidities that present when they occur together as compared to when either condition presents alone. Using data from Fiscal Year 2012 Veteran's Health Administration, all veterans diagnosed with both OUD + CP were compared to those diagnosed with OUD or CP alone on socioenvironmental characteristics, medical and mental health diagnoses, and Veterans Affairs (VA) clinical service use. Veterans with OUD + CP (

Although nicotine from cigarettes is delivered in puff-sized amounts, most preclinical and human intravenous (IV) nicotine studies have used bolus or continuous infusions.To determine the feasibility of a pulsed-nicotine infusion model in smokers.Following overnight abstinence, 12 adult smokers underwent 5 laboratory sessions. Using a crossover design, in each session, participants were assigned to 1 of 5 conditions: (1) high/fast: 1.0 mg nicotine delivered over 5 pulsed-infusions, then 15 saline infusions; (2) high/slow: 1.0 mg nicotine delivered over 20 pulsed-infusions; (3) low/fast: 0.2 mg nicotine delivered over 5 pulsed-infusions, then 15 saline infusions; (4) low/slow: 0.2 mg nicotine delivered over 20 pulsed-infusions; and (5) placebo: Saline delivered over 20 pulsed-infusions. Subjective drug effects, urges to smoke, nicotine withdrawal, and cognitive performance were measured in each session.Both the high/fast and high/slow conditions were associated with greater "head rush" and "high" (p 0.05). The high/fast condition also provided greater suppression of urges to smoke and nicotine withdrawal (p 0.05), indexed by the Questionnaire of Urges to Smoke-Brief, and the Minnesota Nicotine Withdrawal Scale, respectively. The high/fast and high/slow conditions produced greater increases in heart rate (p 0.01) than saline. Finally, there were no main effects of dosing conditions on cognitive performance, indexed by the continuous performance test.These findings demonstrate the feasibility of pulsed-nicotine infusions to model nicotine delivery by smoking. This model could inform future studies testing novel smoking cessation therapies and tobacco regulatory studies testing the impact of nicotine reduction approaches.

There are no approved medications for the treatment of cocaine use disorder (CUD). Modafinil, a cognitive-enhancer with weak stimulant-like effects, has shown promise in initial studies as a treatment for CUD. Its potential efficacy has not been examined in individuals dually dependent on cocaine and opioids.This study examined the efficacy of modafinil, in combination with contingency management (CM), for reducing cocaine and opioid use and improving cognitive function in methadone-stabilized individuals with opioid and cocaine dependence. We conducted a 17-week, double-blind, randomized controlled trial in which participants were randomized to one of four conditions: 1) modafinil + CM; 2) modafinil + yoked-control (YC); 3) placebo +CM; or 4) placebo + YC. Additionally, all subjects received platform treatments of cognitive behavioral therapy (CBT) and methadone. While the original planned sample size was N=160, a total of 91 participants were randomized. The two primary cocaine use outcomes were percentage of urine specimens positive for cocaine and percent of days of self-reported abstinence from cocaine during treatment. Cognitive function, opioid use, and secondary cocaine use outcomes were also considered.Modafinil was well-tolerated with minimal reports of adverse effects. Modafinil was no more effective than placebo in reducing cocaine or opioid use or improving cognitive performance.In the context of a trial with robust control conditions and platform treatments, findings did not provide support for the efficacy of modafinil treatment for the treatment of CUD in methadone-stabilized individuals with dual opioid and cocaine dependence.

Although the efficacy of evidence-based treatments for posttraumatic stress disorder (PTSD) has been well established, high rates of treatment dropout and/or nonresponse or under-response to treatment suggest a need to explore novel treatment approaches. Most current research has focused on DSM-based categorical outcomes as primary indicators of treatment response, which may obscure the phenotypic heterogeneity of PTSD and limit the ability to map symptoms to underlying neurobiology. This systematic review aimed to identify intermediate phenotypes (IPs) of PTSD and evaluate IP sensitivity to PTSD treatments.Five databases were searched for empirical studies published in English between January 1, 2010 and August 1, 2022 examining behavioral and pharmacological PTSD treatment effects on biobehavioral PTSD outcomes.Twenty-two studies met the inclusion criteria. Most studies evaluated behavioral treatment outcomes (The paucity of research combined with the heterogeneity of study methodologies and significant study limitations makes it difficult to draw strong conclusions regarding IP sensitivity to treatment. However, the existing body of research incorporating this framework shows potential for the IP approach to improve the translation of treatment efficacy from clinical trials to clinical settings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The introduction of alternative nicotine and tobacco products (such as e-cigarettes, heat-not-burn devices, nicotine pouches) warrants an updated framework from which to conceptualize tobacco use disorder (TUD). The following review provides considerations for TUD within the context of novel products. Historically, the tobacco industry falsely claimed that cigarettes were not addictive or harmful and that those who smoked simply chose to do so. This generated an inaccurate lay perception that smoking is a free or informed choice. Research on nicotine pharmacology demonstrates the powerful addictive potential of nicotine, which is shaped by dose, speed of delivery, and other constituents generated. In addition, non-pharmacologic reinforcers motivate and maintain tobacco use behaviors for both traditional cigarettes and novel products. The negative consequences of combustible tobacco use are well known; however, these outcomes may differ for alternative products. Strategies used for combustible product cessation may be adapted for novel products, and treatment recommendations for TUD should be made within the context of a harm reduction framework wherein alternative product use may be the desired outcome. Providers must therefore be willing to modify their perceptions of products and treatment recommendations accordingly. Better public health outcomes are accomplished through promotion of abstinence from combustible smoking. For those who cannot wean from nicotine entirely, switching to less risky modes of delivery might be a secondary goal, with an eventual aim of stopping use of the alternative product. Implications: Given the advent of novel, alternative tobacco products, tobacco use disorder (TUD) must be conceptualized within a contemporary framework that includes harm reduction and alternative outcomes. The unique contributions of nicotine pharmacology, non-pharmacologic reinforcers, and consequences of use can be used to inform treatments for TUD with the ultimate goal of improving the health of individuals who use tobacco.

While six U.S. states have already officially authorized cannabinoids to substitute opioids and treat opioid use disorder, the therapeutic benefits of cannabinoids remain unclear, especially when weighted against their adverse effects.We conducted a systematic review of studies examining the association between opioid withdrawal and cannabis use or delta-9-tetrahydrocannabinol (THC) administration. We searched multiple databases from inception to July 30, 2022, and assessed study quality.Eleven studies were identified, with a total of 5330 participants, of whom 64 % were male. Nine observational studies examined the association between cannabis use and opioid withdrawal. Two randomized, placebo-controlled clinical trials (RCTs) investigated the withdrawal-alleviating effects of dronabinol, a synthetic form of THC. Four observational studies found an association between cannabis use and the alleviation of opioid withdrawal; one reported exacerbation of opioid withdrawal symptoms; and four reported no association. RCTs reported that THC alleviated opioid withdrawal, albeit with dose-dependent increases in measures of abuse liability, dysphoria, and tachycardia. There was high heterogeneity in measurements of opioid withdrawal and the type and dose of opioid at baseline.Although there is preliminary evidence that cannabis and its main psychoactive constituent, THC, may alleviate opioid withdrawal, these effects are likely to have a narrow therapeutic window. Further, the potential of cannabinoids to alleviate opioid withdrawal is determined by complex interactions between patient characteristics and pharmacological factors. Collectively, these findings have clinical, methodological, and mechanistic implications for treating opioid withdrawal during cannabinoid use, and for efforts to alleviate opioid withdrawal using non-opioid therapeutics.

Although expanding the availability of buprenorphine—a first-line pharmacotherapy for opioid-use disorder (OUD)—has increased the capacity of healthcare systems to offer treatment, starting this medication is fraught with significant barriers. Standard induction regimens require persons with OUD to taper and discontinue full opioid agonists and experience opioid withdrawal prior to the first dose of buprenorphine. Further, emerging evidence indicates that precipitated withdrawal during induction may impact long-term treatment outcomes. Microinduction is a novel approach that, by harnessing buprenorphine’s unique pharmacological profile, may allow circumventing the needed for prolonged opioid tapers, and reduce the risk of precipitated withdrawal—holding promise to enhance treatment access. In this review, we examine the pharmacological basis for microinduction and appraise the evidence of this approach to improve clinical outcomes among persons with OUD. First, we highlight the potential dose-dependent effects of buprenorphine on two key neuroadaptations at the mu-opioid receptor (MOR)—resensitization and upregulation. We then focus on how microinduction may reverse these chronic MOR neuroadaptations, allowing the maintenance of an adequate opioid tone, and thereby potentially circumventing opioid withdrawal. Second, we describe the clinical evidence available, derived from observational reports and open-label studies, examining the potential efficacy of microinduction. Despite significant heterogeneity—exemplified by variable buprenorphine formulations, daily doses, and schedules of administration—these data provide preliminary support for the feasibility of microinduction. Finally, we provide new mechanistic, methodological, and clinical insights to guide future translational research, as well as randomized, placebo-controlled clinical trials in this compelling agenda of pharmacotherapy development.

RATIONALE: Reducing nicotine content of inhaled tobacco products may prevent nicotine addiction, but the threshold for nicotine reinforcement has not been systematically evaluated in controlled human laboratory studies. OBJECTIVES: The current study uses a novel double-blind placebo-controlled intravenous (IV) nicotine self-administration (NSA) model to determine threshold for subjective effects of nicotine and nicotine reinforcement using a forced choice self-administration procedure. METHODS: Young adults (n = 34) had 5 laboratory sessions after overnight nicotine abstinence. In each session, participants sampled and rated the subjective effects of an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg nicotine/70 kg bodyweight) versus saline (placebo), then were given a total of 10 opportunities to self-administer either the IV dose of nicotine or placebo. RESULTS: Mixed effect models revealed a significant effect of nicotine dose for positive (i.e., “stimulatory” and “pleasurable”; p < .0001) effects, but not “aversive” effects during sampling period. Post hoc comparisons showed that higher doses (i.e., 0.1 and 0.2 mg) were associated with greater stimulatory, pleasurable, and physiological effects than placebo and lower doses. Mixed effect models revealed that only the highest dose (i.e., 0.2 mg) was consistently preferred over placebo. Sex differences were generally weak (p = .03–.05). CONCLUSIONS: Using our IV nicotine NSA model, the threshold for detecting positive effects of nicotine in young adult smokers is about 0.1 mg, but a higher dose of nicotine, 0.2 mg, is required to produce a consistent nicotine reinforcement. Regarding the regulatory impact, our findings further support the value of nicotine reinforcement threshold as a tobacco regulatory target.

Introduction Although exogenous progesterone may hold promise as a treatment for nicotine use disorders, it is unclear whether it is similarly effective in males and females. This study examined the effects of progesterone on nicotine use disorder comprehensively using behavioral, psychological, and neural measures in male and female smokers exposed to brief abstinence. Aims and Methods Thirty-three male and 33 female non-treatment-seeking smokers participated in a double-blind, randomized, placebo-controlled crossover study of 200 mg of progesterone or placebo daily over a four-day abstinence period. Smoking behavior and subjective effects of nicotine were assessed at baseline and after final drug administration. Nicotine withdrawal, smoking urges, mood states, and neural response to smoking cues were measured at baseline, after the first drug administration, and after the final drug administration. Results No main effect of drug (progesterone vs. placebo) emerged for any outcome. Significant sex by drug interactions emerged for nicotine withdrawal (p = .020), perceived strength of nicotine (p = .040), and perceived bad effects of nicotine (p = .029). Males receiving progesterone reported worse nicotine withdrawal (p = .046) and a trend towards decreased bad effects of nicotine (p = .070). Males on progesterone also reported greater tension and anxiety relative to placebo (p = .021). Females on progesterone perceived nicotine’s effects as being stronger relative to placebo (p = .046). Conclusions Progesterone causes sex-dependent effects on smoking-related outcomes during brief abstinence. Specifically, progesterone in males may increase rather than decrease nicotine withdrawal and negative affect during abstinence, potentially hindering efforts to quit smoking. Implications In male and female smokers undergoing a brief period of abstinence, we examined the effects of progesterone on smoking outcomes. While progesterone had limited effects in female smokers, in males, it worsened nicotine withdrawal and negative affect. Our findings emphasize the importance of analyzing sex differences in future studies examining progesterone as a potential treatment and suggest that progesterone in males could potentially exacerbate aspects of nicotine dependence. Clinicaltrials.gov registration NCT01954966. https://clinicaltrials.gov/ct2/show/NCT01954966

Faster delivery rate enhances the abuse potential of drugs of abuse, yet systematic studies on the impact of delivery rate on the acute effects of nicotine in humans are lacking. Using an intravenous (IV) nicotine infusion procedure that allows precise control of rate of delivery, we examined the impact of nicotine delivery rate on the positive subjective drug effects, smoking urges, withdrawal, heart rate, blood pressure and attention function in smokers. Twenty-four male and female (ages 21 to 35) dependent smokers attended five experimental sessions, following overnight abstinence from smoking. Using a crossover design, participants attended 5 sessions, where they were assigned to a random sequence of saline infusion or 1 mg nicotine delivered over 1, 2.5, 5, or 10 minutes at rates of 1, 0.4, 0.2, or 0.1 mg/minute, respectively. The positive subjective effects of nicotine were most robust under the two faster delivery rate conditions, 1 and 0.4 mg nicotine/minute. In contrast, all nicotine delivery rates were equally more effective than saline in alleviating urges to smoke. Likewise, nicotine-induced heart rate increases did not vary with the rate of nicotine delivery. Lastly, the cognitive enhancing effects of nicotine were observed only under the two slowest delivery rate conditions – 0.1 and 0.2 mg nicotine/minute. Collectively, these findings support the critical role of delivery rate in optimizing nicotine’s abuse potential vs. potential therapeutic effects and have timely implications for developing novel therapeutics for nicotine dependence, as well as for tobacco regulatory science.

This secondary analysis sought to determine if plasma menthol glucuronide (MG) concentrations predict changes in three outcomes, subjective drug effects, urges to smoke, and heart rate, following concurrent inhaled menthol and intravenous nicotine. A total of 45 menthol and non-menthol cigarettes smokers (36 male, nine female, 20 Black, and 23 White) were included in this double-blind, placebo-controlled study. Across three test sessions, participants were assigned to a different flavor condition for each session: 0% (no menthol), 0.5%, or 3.2% menthol. In each test session, participants received in a random order one intravenous delivery of saline and two intravenous deliveries of nicotine (0.25 mg/70 kg and 0.5 mg/70 kg), each 1 h apart, concurrent with menthol delivery by e-cigarettes. The main outcomes were subjective drug effects, urges to smoke, and heart rate. The results showed that following e-cigarette inhalation, changes in plasma MG concentrations or “menthol boost” increased proportionally to the menthol concentration in the e-liquids. While changes in plasma MG concentrations were not predictive of increases in heart rate or subjective drug effects that are reflective of acute effects from nicotine (i.e., feel good effects, stimulated, aversive effects), they were predictive of cooling effect, a typical effect of menthol, but only in menthol smokers in the absence of concurrent active nicotine infusion. These findings demonstrate the utility of plasma MG as a biomarker both for acute menthol exposure by e-cigarette inhalation and for the examination of the concentration-dependent behavioral and physiological effects of menthol in humans.

TR and AF have received supports from the Cognitive Science and Technologies Council (CSTC) of Iran and Tehran University of Medical Sciences (TUMS) for the ongoing Clinical Trial with NECOREDA. Background Impaired cognitive functions, particularly executive function, predicts poor treatment success in people with substance use disorders. The current study investigated the effect of receiving adjunct cognitive rehabilitation and baseline executive function (EF) measures on treatment response among people with opioid use disorder (OUD). Method The analysis sample consisted of 113 participants with OUD who were discharged from a compulsory court-mandated methadone maintenance treatment (MMT) and followed for 3 months. We used the Backward digit span/Auditory verbal learning, Stroop, and Trail making tests to assess the three measures of EF, including working memory, inhibition, and shifting, respectively. Treatment response was operationalized as (1) treatment retention and (2) the number of positive urine tests for morphine during 3-month follow-up periods. The study used Cox's proportional hazards model and linear mixed model to identify predictive factors. Results Lower Stroop interference scores predicted increased length of stay in treatment (χ2 = 33.15, P

Introduction: Opioid use disorder (OUD) has risen globally and is exerting an enormous toll on public health in many countries, particularly in the United States (US). Buprenorphine (BUP) has become one of the mainstays of pharmacological treatment for OUD and newer delivery methods have been developed to improve its effectiveness in treatment. Areas covered: We provide a review of BUP products available for OUD, with a focus on the newer long-acting formulations. A literature search was conducted using PubMed, Google Scholar, and ClinicalTrials.gov to find randomized clinical trials of long-acting BUP products. Four randomized clinical trials were found: two with BUP implant and two with subcutaneous injectable BUP. Expert opinion: In these clinical trials, new BUP formulations were found to be non-inferior to sublingual (SL) BUP and more effective than placebo in reducing opioid use. Longer-acting formulations can improve flexibility in dosing but superiority over existing SL BUP with regards to outcomes needs to be ascertained. There is a need for more comparative studies between longer-acting BUP formulations and currently available SL BUP. Future studies should also include other clinically meaningful outcomes such as quality of life measures, long-term remission rates, and cost-effectiveness.

Background and objectives Concurrent use of cocaine and opioids is a persistent and challenging problem, particularly within methadone maintenance settings, and there are no approved pharmacotherapies for this population. Galantamine, a cholinesterase inhibitor, was found in a randomized clinical trial to reduce cocaine use among methadone-maintained individuals who were also cocaine dependent. Because of the potential of galantamine to reduce multiple drugs of abuse, it may also reduce opioid use. Methods We conducted a secondary analysis of a randomized, double-blind, placebo-controlled trial of 120 methadone-maintained individuals with concurrent cocaine dependence. Participants were randomized to galantamine or placebo in a 12-week trial with a 6-month follow-up (97% of intention to treat sample reached for final follow-up). Results There was a significant main effect for galantamine over placebo on percent of urine specimens that were negative for opioids, both within treatment (77% for galantamine vs 62% for placebo, F = 5.0, P = 0.027) and through a 6-month follow-up (81% vs 59%, respectively, F = 10.8, P = 0.001). This effect was seen regardless of whether participants used nonprescribed opioids during the baseline period. Galantamine effects were seen early in treatment, with participants in placebo submitting the first opioid-positive urine specimen significantly sooner than participants in galantamine (median day 15 vs 53, Wilcoxon = 5.7, P = 0.02). Conclusions and scientific significance If these results are supported in future trials, galantamine may hold promise across multiple drugs of abuse, including opioids. (Am J Addict 2019;28:238-245).

Background Electronic cigarettes (EC) may aid some smokers in reducing combustible tobacco use. Smokers with psychiatric co-morbidities tend to have higher nicotine dependence and worse outcomes, so may particularly benefit from alternative cessation aids. EC characteristics, like nicotine level and flavor, may influence EC's appeal to smokers. Nicotine level may impact EC's efficacy in reducing combustible cigarette use. Methods Non-treatment-seeking cigarette smokers with medical/psychiatric co-morbidities rated ‘liking’ of ECs varying in nicotine level (12 mg, 24 mg) and flavor (menthol, ‘slim’-tobacco, ‘burley’-tobacco), during an open-label Choice Procedure. Smokers (N = 43) chose ECs for a 4-week take-home-trial, and used EC and/or combustible cigarettes as they wished. Analyses examined ratings and choice by nicotine level and flavor, and the relationship between consistent take-home choice of 12 mg versus 24 mg baseline demographic/smoking characteristics, and outcomes (cigarettes/day, nicotine intake, motivation to quit smoking) during take-home-trial and one-month follow-up. Results Smokers who chose menthol-flavor, tobacco-flavor and/or 24 mg nicotine e-liquids for the first take-home week rated these conditions as more ‘liked’ than alternative options, at baseline. Groups who chose 12 mg versus 24 mg throughout the take-home trial did not significantly differ on baseline characteristics, or smoking-related outcomes within the take-home trial, however, motivation to quit smoking increased more from baseline to one-month follow-up in choosers of higher nicotine (24 mg) ECs. Conclusions Associations between subjective ratings and subsequent choice support feasibility of open-label choice-procedures in EC trials. Access to 12 mg or 24 mg nicotine ECs was associated with reduced smoking, and 24 mg ECs with increased motivation to quit smoking in smokers with medical/psychiatric co-morbidities.

INTRODUCTION: Electronic cigarettes (e-cigarettes) are popular among college students, who display risky alcohol use patterns. However, little is known about patterns of co-use of e-cigarettes and alcohol. Further, relationships between e-cigarette use and mental illness among college students are unclear. METHODS: College student participants (N=631) at a northeastern U.S. university were invited via email to participate in a survey about e-cigarettes and alcohol use. Mental health was self-reported diagnosis of psychiatric (depression, bipolar disorder, schizophrenia, PTSD, anxiety disorder, personality disorder), and substance (alcohol and other drug) use disorders. Current use of e-cigarette, combustible cigarette, and other tobacco products were assessed via self-reported past 30-day use frequency. Alcohol consumption was assessed via number of self-reported standard alcoholic beverages consumed during a typical drinking episode. Participants also reported regarding co-use of alcohol, e-cigarettes and/or combustible cigarettes. Participants were categorized as non-drinkers, moderate drinkers or binge drinkers, and associations between e-cigarette use, drinking patterns and mental health diagnoses were examined RESULTS: E-cigarette use was associated with drinking alcohol χ(2)=18.62, p

Alcohol has both acute and chronic effects on neuroimmune signaling, including triggering pro-inflammatory cytokine release by microglia. Minocycline, a second-generation tetracycline antibiotic, inhibits microglial activation and reduces neuroinflammation in preclinical studies. In mice, minocycline also reduces ethanol intake, attenuates ethanol-induced conditioned place preference, and inhibits ethanol-induced microglial activation and pro-inflammatory cytokine release. Here, for the first time, we tested the effects of minocycline on subjective response to ethanol and acute ethanol-induced inflammation in humans. Forty-eight heavy drinkers participated in a double-blind, placebo-controlled trial in which they were randomized to receive placebo, 100 mg, or 200 mg of minocycline for 10 days. Each subject then underwent two experimental sessions in which they were given a fixed dose of intravenous ethanol using a “clamp” procedure (100 mg%) or placebo (normal saline) on days 8 and 10 of treatment. Minocycline was well tolerated, but there was no effect of either dose of minocycline on subjective response to ethanol or ethanol-induced craving; minocycline effects on cognitive function seem to interact with age. Minocycline treatment did not alter serum cytokine levels at baseline or during ethanol-exposure, although certain baseline cytokine levels predict sedative response to ethanol. These findings indicate that a short-term treatment with minocycline may not alter ethanol-related inflammation or subjective response to ethanol in humans. Further research is needed to identify pharmacological agents with robust effects on ethanol-induced inflammation to determine whether neuroimmune modulation represents a viable treatment strategy for alcohol use disorder.

Background:Veterans are at high risk for suicide; emotion dysregulation may confer additional risk. Dialectical behaviour therapy (DBT) is a well-supported intervention for suicide attempt reduction in individuals with emotion dysregulation, but is complex and multi-component. The skills group component of DBT (DBT-SG) has been associated with reduced suicidal ideation and emotion dysregulation. DBT-SG for Veterans at risk for suicide has not been studied.Aims:This study sought to evaluate the feasibility and acceptability of DBT-SG in Veterans and to gather preliminary evidence for its efficacy in reducing suicidal ideation and emotion dysregulation and increasing coping skills.Method:Veterans with suicidal ideation and emotion dysregulation (N = 17) enrolled in an uncontrolled pilot study of a 26-week DBT-SG as an adjunct to mental health care-as-usual.Results:Veterans attended an average 66% of DBT-SG sessions. Both Veterans and their primary mental health providers believed DBT-SG promoted Veterans’ use of coping skills to reduce suicide risk, and they were satisfied with the treatment. Paired sample t-tests comparing baseline scores with later scores indicated suicidal ideation and emotion dysregulation decreased at post-treatment (d = 1.88, 2.75, respectively) and stayed reduced at 3-month follow-up (d = 2.08, 2.59, respectively). Likewise, skillful coping increased at post-treatment (d = 0.85) and was maintained at follow-up (d = 0.91).Conclusions:An uncontrolled pilot study indicated DBT-SG was feasible, acceptable, and demonstrated potential efficacy in reducing suicidal ideation and emotion dysregulation among Veterans. A randomized controlled study of DBT-SG with Veterans at risk for suicide is warranted.

Basic science studies indicate that menthol can enhance the cognitive effects of nicotine to increase nicotine dependence; however, the effect of menthol and nicotine on cognitive functioning among humans has been understudied. This double-blind, placebo-controlled study examined the dose-dependent effects of inhaled menthol flavoring and intravenous nicotine on cognitive task performance. Twenty menthol (MS) and 18 non-menthol (NMS) cigarette preferring, young-adult smokers (21% female; 7.9% Hispanic, 44.7% Non-Hispanic/White, 47.4% Non-Hispanic/Black) completed three sessions with randomized order of menthol flavoring (between-sessions: 0.0%/tobacco control, 0.5%/low, 3.2%/high) and intravenous nicotine (within-session: 0.0 mg/saline control, 0.25 mg/low, 0.5 mg/high). After each administration, participants completed three cognitive tasks: Continuous Performance Task (CPT), Mathematical Processing Task (MPT), and Stroop Task. Mixed effects models were used to examine interactive effects of cigarette type preference and menthol and nicotine doses. MS vs. NMS had decreased accuracy on CPT and MPT and efficiency during Stroop. No significant effects of cigarette type preference by menthol or nicotine were found for any task. Significant effects of nicotine by menthol were found during Stroop, where participants had greater accuracy for high nicotine compared to saline during the low menthol session. Significant effects of menthol by timepoint were seen during Stroop, where participants improved across timepoints during the low menthol session. Findings did not support significant effects of inhaled menthol, alone or with nicotine, on cognitive performance. Further research clarifying the impact of varying menthol and nicotine levels in nicotine products may help to elucidate menthol’s role in smoking sustainment.

OBJECTIVE: Opioid use disorder (OUD) is a significant problem among US veterans with increasing rates of OUD and overdose, and thus has substantial importance for service delivery within the Veterans Health Administration (VHA). Among individuals with OUD, several sex-specific differences have begun to emerge regarding co-occurring medical, psychiatric and pain-related diagnoses. The rates of such multimorbidities are likely to vary between men and women with OUD and may have important implications for treatment within the VHA but have not yet been studied. METHODS: The present study utilized a data set that included all veterans receiving VHA health care during Fiscal Year (FY) 2012 (October 1, 2011 through September 30, 2012), who were diagnosed during the year with opioid dependence or abuse. VHA patients diagnosed with OUD nationwide in FY 2012 were compared by sex on proportions with OUD, and among those with OUD, on sociodemographic characteristics, medical, psychiatric and pain-related diagnoses, as well as on service use, and psychotropic and opioid agonist prescription fills. RESULTS: During FY 2012, 48,408 veterans were diagnosed with OUD, 5.77% of whom were women. Among those veterans with OUD, few sociodemographic differences were observed between sexes. Female veterans had a higher rate of psychiatric diagnoses, notably mood, anxiety and personality disorders, as well as higher rates of pain-related diagnoses, such as headaches and fibromyalgia, while male veterans were more likely to have concurrent, severe medical co-morbidities, including hepatic disease, HIV, cancers, peripheral vascular disease, diabetes and related complications, and renal disease. There were few differences in health service utilization, with women reporting greater receipt of prescriptions for anxiolytic/sedative/hypnotics, stimulants and lithium. Men and women did not differ in receipt of opioid agonist medications or mental health/substance use treatments. CONCLUSIONS: There are substantial sex-specific differences in patterns of multimorbidity among veterans with OUD, spanning medical, psychiatric and pain-related diagnoses. These results illustrate the need to view OUD as a multimorbid condition and design interventions to target such multimorbidities. The present study highlights the potential benefits of sex-specific treatment and prevention efforts among female veterans with OUD and related co-occurring disorders.

Background Treating acute pain among persons with opioid use disorder (OUD) on opioid agonist therapy (OAT) is complex, and the therapeutic benefits of opioids remain unclear when weighted against their abuse potential and respiratory depressant effects. Methods We conducted a systematic review of experimental pain studies examining opioid-induced analgesia among persons with OUD on OAT. We searched multiple databases from inception to July 30, 2021. Study quality was assessed by previously established validity measures. Results Nine studies were identified, with a total of 225 participants, of whom 63% were male, and 37% were female. Six studies included methadone-maintained persons with OUD; four studies included buprenorphine-maintained persons with OUD; and three studies included healthy persons as comparison groups. Either additional doses of OAT or other opioids – morphine, oxycodone, hydromorphone, or remifentanil – were administered. In seven studies, persons with OUD on OAT did not experience analgesia, despite receiving opioid doses up to 20 times greater than those clinically used to treat severe pain among the opioid naive. Conversely, in two studies, high-potency opioids did produce analgesia, albeit with greater abuse potential. Notably, persons with OUD on OAT remained vulnerable to respiratory depression. Conclusions Although persons with OUD on OAT can derive analgesic effects from opioids, high-potency compounds may be required to achieve clinically significant pain relief. Further, persons with OUD on OAT may remain vulnerable to opioid-induced abuse potential and respiratory depression. Together, these finding have clinical, methodological, and mechanistic implications for the treatment of acute pain in the context of OAT.

Objectives Opioid use disorder (OUD) is a public health emergency. Evidence suggests that posttraumatic stress disorder (PTSD) is common among individuals with OUD; however, few studies evaluate whether concurrent diagnoses affect treatment outcomes. This review examines the impact of concurrent diagnoses of OUD and PTSD on treatment outcomes. Methods A search was performed using articles identified through June 30, 2020 in PubMed, PsycINFO, and EMBASE. Included peer-reviewed articles evaluated individuals with OUD and a PTSD diagnosis via standardized assessment and/or medical record diagnoses, and reported relationships between diagnosis and treatment outcomes and/or other psychiatric conditions. Results Out of 412 articles, 17 studies met inclusion criteria for this review (from 13 databases). Articles included had a total of n = 2190 with OUD, with n = 79 non-OUD comparison participants. Studies examining individuals with OUD revealed comorbid PTSD was associated with more severe addiction, higher rates of depression, attempted suicide, and psychosocial problems. Conclusions Among individuals with OUD, presence of PTSD is associated with multiple mental health problems. The impact of PTSD on drug use is inconclusive. Although only 5 studies examined psychosocial PTSD treatment, all found PTSD-focused treatment to be effective for those with comorbid OUD. Overall, results suggest the need to better identify PTSD among those with OUD, and to develop and evaluate interventions that are brief, integrative, and easy to implement in clinical settings.

The clinical features and neurobiology of pain and opioid use disorder (OUD) are inextricably linked. Despite emerging evidence supporting the negative impact of ongoing pain in the treatment of OUD, the pharmacological management of pain in the presence of OUD has received limited attention. We sought to systematically review the studies investigating pharmacotherapies for pain among persons with OUD. Eligible studies had participants with OUD and outcomes including evoked or spontaneous pain. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Out of 1,097 studies that met the search criteria, 12 studies provided data relevant to the research question-five laboratory studies and seven clinical trials. Random effects pooled estimates suggested no significant difference between groups at baseline but a response favoring the active treatment group over placebo, with nonsignificant heterogeneity between studies. Findings from these studies provide preliminary evidence for analgesic and antihyperalgesic effects of gabapentin, GABA agonists, and NMDA antagonists among persons with OUD. To establish the tradeoffs between the analgesic effects and abuse liability of these compounds, further well-controlled clinical trials are required among persons with OUD. This review also underscores the need for methodological enhancement in drug development for pain in OUD. Future research should address the clinical and neurobiological overlap between pain- and addiction-related phenomena. Transdisciplinary approaches may identify biomarkers of these shared phenomena and their neural substrates. The development of novel therapeutics for pain in OUD may be accelerated by such integration of pain and addiction research.

Menthol is the only available flavor in combusted tobacco cigarettes; however, e-cigarettes are available in thousands of flavors. Research on flavors and rewarding properties of nicotine is limited. The present study sought to examine the acute rewarding effects of flavors inhaled from an e-cigarette, in combination with intravenous (IV) nicotine among cigarette smokers. In the present study, 24 menthol-preferring young adult (aged 18 to 30) cigarette smokers were tested under 3 different e-cigarette flavor conditions (menthol, green apple, or menthol + green apple) in a within-subject cross-over design. During each test session, each participant received 3 IV infusions (saline, 0.25 mg/70 kg nicotine, 0.5 mg/70 kg nicotine) administered 1 hr apart. The main outcome measures assessed cardiovascular, subjective, and cognitive domains. Compared with green apple or green apple + menthol, menthol produced higher ratings of "cooling" (ps < 0.01). Craving was rated higher following administration of green apple and the combined menthol + apple flavor compared to menthol alone (ps < 0.05). As expected, IV-nicotine dose-dependently increased the ratings of subjective liking/disliking and peak heart rate, improved cognitive performance, and reduced smoking urges (all ps < 0.05). These subjective, cognitive, and physiological effects of nicotine were not affected by any flavor condition. The present findings did not support an interaction between IV-nicotine dose and inhaled flavor for acute effects of nicotine. Green apple flavor, alone or in combination with menthol, could result in higher craving or insufficiently alleviate craving, relative to menthol flavor alone. Additional research is warranted to examine extended exposure to inhaled flavors on the rewarding and addictive effects of nicotine. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objectives: Studies suggest that men and women have different vulnerabilities to a number of substance use disorders (SUDs). We examined whether differences between women and men with opioid use disorder (OUD) are significantly different from those without OUD for selected sociodemographic and health outcomes. Methods: We used a cross-sectional survey design using data from 2012 to 2013 National Epidemiological Survey on Alcohol and Related Conditions Wave III, which surveyed nationally representative samples of non-institutionalized adults (n = 36,309 unweighted). Past-year OUD and other behavioral co-morbidities were defined using DSM-5 criteria. In bivariate analyses, we investigated sex differences in socio-demographic factors, behavioral co-morbidities, pain, and health-related quality of life (HRQOL) between women and men with past-year OUD, and then those without past-year OUD. We further used logistic regression analyses to evaluate interactions between effect of sex and past-year OUD status on behavioral co-morbidities, pain, and HRQOL. Results: When extrapolated, about 2.1 million US adults met diagnostic criteria for past-year OUD. Women with OUD had a higher likelihood of having several past-year psychiatric disorders, and a lower likelihood of having any past-year SUDs compared to male counterparts. However, similar relationships were observed among those without OUD and significant interaction effects were not found on behavioral co-morbidities, pain, and HRQOL, indicating that general sex differences are not specific to OUD. Conclusions: Although sex differences are not specific to OUD, concurrent disorders are not uncommon among women, as well as men, with OUD. There is a need to treat concurrent behavioral health conditions from a multimorbidity perspective in the treatment of OUD in both sexes.

To evaluate measurement and associations between pain severity and opioid craving in individuals with chronic pain on long-term opioid therapy and/or with opioid use disorder.. Systematic review of randomized controlled trials and observational studies.. The PubMed, EMBASE, and PsycINFO databases were searched in October 2018. Eligible studies evaluated pain severity and opioid craving in individuals with chronic pain on long-term opioid therapy and/or with opioid use disorder. Two reviewers independently screened eligible studies, assessed risk of bias, and extracted data.Of 625 studies, 16 fulfilled the inclusion/exclusion criteria of this review and were grouped by diagnostic focus (i.e., chronic pain on long-term opioid therapy, opioid use disorder, or both). Methods of assessment varied considerably across studies, especially with respect to opioid craving in chronic pain populations. Mean levels of pain were at what is considered moderate to severe in individuals with chronic pain and/or opioid use disorder. There was a modest positive relationship between pain and opioid craving that was more pronounced in studies of individuals with opioid use disorder compared with those with chronic pain on long-term opioid therapy.Pain severity and opioid craving are likely related, but inconsistencies in measurement limit confidence. The overall quality of evidence is moderate, and careful consideration of how pain and craving are assessed in both chronic pain and opioid use disorder patients is warranted.

RATIONALE: The nicotine delivery rate is a key feature of tobacco product design, yet there have been limited human studies examining the effects of nicotine as a function of delivery rate. OBJECTIVE: We developed an intravenous nicotine infusion protocol to evaluate differential effects of nicotine delivery rate on subjective drug effects, smoking urges, abstinence symptoms, heart rate and blood pressure. METHODS: Eighteen non-treatment seeking, overnight abstinent male and female smokers (18 to 30 year-old), who smoked ≥ 5 cigarettes per day for the past year completed four sessions in which they were randomly assigned to a saline infusion, or a 1 mg per 70 kg body weight dose of nicotine delivered over 1, 5 or 10 minutes at rates of 0.24, 0.048 or 0.024 μg/kg/second, respectively. RESULTS: Smoking urges, as assessed by the Brief Questionnaire of Smoking Urges, were reduced relative to placebo for the 1 and 5 min infusion, but not the 10 min infusion. Although the 1 and 5 min infusions reduced smoking urges to a similar extent, the 1 min infusion induced a greater heart rate and blood pressure increase. Changes to subjective drug effects, heart rate and blood pressure delineate the differential effects of nicotine delivery rate for these outcomes. CONCLUSIONS: We have characterized the delivery rate-response curve for a nicotine dose that is roughly the amount of nicotine (~1 mg) delivered by smoking a standard tobacco cigarette. Our findings reinforce the importance of nicotine delivery rate when evaluating the potential effects of nicotine from tobacco products.

Substance use disorders (SUDs) remain a significant health problem, and novel pharmacological targets are needed to improve treatment outcomes. Given that chronic use of alcohol, cocaine, methamphetamine, cannabis, and tobacco is often associated with significant cognitive deficits, pharmacological treatments targeting these impairments may offer a new approach to treat SUDs. This chapter reviews the rationale for utilizing pharmacological cognitive enhancement as a treatment strategy for SUDs and presents potential mechanisms to target in treatment to address the impaired cognitive functioning related to SUDs. Furthermore, the chapter presents discussion of possible candidate medications for cognitive enhancement for substance use.

Objective:Opioid use disorder (OUD) in the United States has surged, with an estimated 2.5 million needing treatment. The aim of this article is to provide a clinical overview of the key pharmacolo...

Background The theoretical benefits of naltrexone as a treatment for opioid use disorder (e.g., safety, non-addictive, low risk of diversion) stand in sharp contrast to its disappointing record on retention in most samples. The relationship of uncomfortable physical and dysphoric symptoms to retention on naltrexone is a controversial and under-studied issue. Methods Using data from a randomized controlled trial of voucher-based contingency management and support from a significant other to enhance retention on oral naltrexone, we compared self-reported somatic and dysphoric symptoms, measured weekly, for individuals who were retained on naltrexone through the 12-week trial (n = 50) versus those who dropped out (n = 70). Results There were no differences between participants who completed treatment and those who dropped out on multiple baseline characteristics, including somatic or affective symptoms prior to treatment. However, whether analyzed cross-sectionally or over time, participants who dropped out consistently reported higher rates of somatic symptoms, particularly difficulty sleeping, as well as affective symptoms, including multiple indicators of depression, anxiety, and anhedonia. Conclusions Although the smaller group of participants who were retained on oral naltrexone for 12 weeks reported decreasing physical and affective discomfort over time, there was substantial evidence that those who dropped out experienced continued and significant levels of distress. Individuals who report physical or affective distress while taking naltrexone may be at higher risk of dropout.

Alcohol use among women is increasing relative to men but no study has compared rates and characteristics of women with alcohol use disorder (AUD) to men among Veterans Health Administration (VHA) service users. To compare male and female VHA service users on rates of AUD, and among those with AUD, on sociodemographic characteristics, medical and physical comorbidities, and service and medication use national VHA data from fiscal year (FY) 2012 were used to identify Veterans diagnosed with AUD. Bivariate analyses evaluate gender differences in: sociodemographic characteristics; comorbid medical and psychiatric diagnoses; service use and psychotropic prescription fills. Multivariate stepwise logistic regression was used to identify a parsimonious set of differences. About 13,797 of all 349,430 women served by VHA in FY 2012 (3.94%) were diagnosed with AUD as compared to 331,407 of 5,102,877 men (6.50%) for a risk ratio of 0.608 for AUD among women. Women were younger, more likely to have served in recent Middle East conflicts and had more comorbid psychiatric and substance use diagnoses than men. They filled fewer psychotropic prescriptions (after taking greater number of psychiatric diagnoses in to account), but were more likely to fill a prescription for naltrexone than men. Women had fewer comorbid medical diagnoses than men. Women Veterans with an AUD have higher rates of psychiatric comorbidities than men, highlighting the need for better integration of treatment for AUD and comorbid psychiatric conditions, and suggesting different pathways and potential interventions for AUD in women.

Background Opioid use in the United States is a national public health emergency. The primary treatment for opioid use disorder (OUD) is medication assisted treatment (MAT). Although effective in improving treatment outcomes in OUD, there is a need to develop behavioral treatments adjunctive to MAT. The current study investigates attentional bias in OUD as a possible target for adjunctive behavioral treatments. Methods Comprehensive literature searches of psychological, medical, and educational databases were conducted through October 2017. Eligible peer-reviewed studies evaluated attentional bias in opioid users, used a task to evaluate attentional bias that included active response to study stimuli, calculated attention bias by comparing response to drug and neutral stimuli, and could isolate attentional bias specific to opioid versus neutral stimuli from bias to other salient stimuli. Conclusions The results of our systematic review and meta-analysis suggest that individuals with OUD exhibit robust attentional bias to opioid cues, even when engaged in MAT. Interventions that reduce attentional bias may be a useful adjunct to MAT.

Opioid overdoses recently became the leading cause of accidental death in the US, marking an increase in the severity of the opioid use disorder (OUD) epidemic that is impacting global health. Current treatment protocols for OUD are limited to opioid medications, including methadone, buprenorphine, and naltrexone. While these medications are effective in many cases, new treatments are required to more effectively address the rising societal and interpersonal costs associated with OUD. In this article, we review the opioid and cholinergic systems, and examine the potential of acetylcholine (ACh) as a treatment target for OUD. The cholinergic system includes enzymes that synthesize and degrade ACh and receptors that mediate the effects of ACh. ACh is involved in many central nervous system functions that are critical to the development and maintenance of OUD, such as reward and cognition. Medications that target the cholinergic system have been approved for the treatment of Alzheimer's disease, tobacco use disorder, and nausea. Clinical and preclinical studies suggest that medications such as cholinesterase inhibitors and scopolamine, which target components of the cholinergic system, show promise for the treatment of OUD and further investigations are warranted.