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PurposeWe aimed to estimate health state utility values (HSUVs) for the key health states found in opioid use disorder (OUD) cost-effectiveness models in the published literature.MethodsData obtained from six trials representing 1,777 individuals with OUD. We implemented mapping algorithms to harmonize data from different measures of quality of life (the SF-12 Versions 1 and 2 and the EQ-5D-3 L). We performed a regression analysis to quantify the relationship between HSUVs and the following variables: days of extra-medical opioid use in the past 30 days, injecting behaviors, treatment with medications for OUD, HIV status, and age. A secondary analysis explored the impact of opioid withdrawal symptoms.ResultsThere were statistically significant reductions in HSUVs associated with extra-medical opioid use (-0.002 (95% CI [-0.003,-0.0001]) to -0.003 (95% CI [-0.005,-0.002]) per additional day of heroin or other opiate use, respectively), drug injecting compared to not injecting (-0.043 (95% CI [-0.079,-0.006])), HIV-positive diagnosis compared to no diagnosis (-0.074 (95% CI [-0.143,-0.005])), and age (-0.001 per year (95% CI [-0.003,-0.0002])). Parameters associated with medications for OUD treatment were not statistically significant after controlling for extra-medical opioid use (0.0131 (95% CI [-0.0479,0.0769])), in line with prior studies. The secondary analysis revealed that withdrawal symptoms are a fundamental driver of HSUVs, with predictions of 0.817 (95% CI [0.768, 0.858]), 0.705 (95% CI [0.607, 0.786]), and 0.367 (95% CI [0.180, 0.575]) for moderate, severe, and worst level of symptoms, respectively.ConclusionWe observed HSUVs for OUD that were higher than those from previous studies that had been conducted without input from people living with the condition.

Early adolescent drinking onset is linked to myriad negative consequences. Using the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) baseline to year 8 data, this study (1) leveraged best subsets selection and Cox Proportional Hazards regressions to identify the most robust predictors of adolescent first and regular drinking onset, and (2) examined the clinical utility of drinking onset in forecasting later binge drinking and withdrawal effects. Baseline predictors included youth psychodevelopmental characteristics, cognition, brain structure, family, peer, and neighborhood domains. Participants (N=538) were alcohol-naïve at baseline. The strongest predictors of first and regular drinking onset were positive alcohol expectancies (Hazard Ratios [HRs]=1.67-1.87), easy home alcohol access (HRs=1.62-1.67), more parental solicitation (e.g., inquiring about activities; HRs=1.72-1.76), and less parental control and knowledge (HRs=.72-.73). Robust linear regressions showed earlier first and regular drinking onset predicted earlier transition into binge and regular binge drinking (βs=0.57-0.95). Zero-inflated Poisson regressions revealed that delayed first and regular drinking increased the likelihood (Incidence Rate Ratios [IRR]=1.62 and IRR=1.29, respectively) of never experiencing withdrawal. Findings identified behavioral and environmental factors predicting temporal paths to youthful drinking, dissociated first from regular drinking initiation, and revealed adverse sequelae of younger drinking initiation, supporting efforts to delay drinking onset.

Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal-directed control over reward seeking. Specifically, morphine-withdrawn rats were impaired in using current reward value to select actions both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

Rationale: The newly emerging synthetic cannabinoids (SCs) 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201 have been observed to produce effects by activating cannabinoid type 1 (CB1) receptors. Nevertheless, the pharmacological effects and potential for abuse of these three substances remain to be studied. These substances have yet to be regulated in many countries. Objectives: We investigated the safety, pharmacological effects, rewarding effects, and cannabinoid withdrawal of 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201. Methods: This study evaluated the drug safety and the cannabinoid-specific pharmacological effects of the three substances through acute toxicity experiments (in which the LD50 of each substance was obtained) and tetrad experiments (comprising assessments of hypothermia, analgesia, locomotion inhibition, and catalepsy). Furthermore, the conditioned place preference (CPP) experiments and withdrawal experiments were conducted to evaluate the rewarding effect and cannabinoid withdrawal potential of the substances in question. Results: The results demonstrated that all three drugs exhibited certain acute toxic effects and could potentially induce tetrad effects. The data were analyzed using non-linear regression, and the corresponding ED50 values and 95% confidence intervals (CI) were obtained. The rank order of potency was determined to be CUMYL-PEGACLONE > 5F-EDMB-PICA > NM-2201. In the CPP experiments, it was demonstrated that 5F-EDMB-PICA significantly induced an increase in CPP score at a dose of 0.3 mg/kg, while NM-2201 caused an increase in CPP score and a significant aversion effect at a dose of 2 and 3 mg/kg, respectively. It is noteworthy that all three types of SCs were observed to produce a significant biphasic effect, indicating that CPP scores were biphasic for all compounds. Following the administration of the CB1 receptor antagonist rimonabant, a notable increase in head twitches and paw tremors was observed, indicating that these three SCs induce cannabinoid withdrawal through the mediation of CB1 receptors. Conclusions: The results of this study indicated that these SCs possess cannabinoid-specific pharmacological effects and abuse potential, which provides substantial experimental data to support the future regulation of these substances. [ABSTRACT FROM AUTHOR]

The management of sedation in critically ill adults poses a unique challenge to clinicians. Dexmedetomidine, an α2 agonist, has a unique mechanism and favorable pharmacokinetics, making it an attractive intravenous option for sedation and delirium in the intensive care unit. However, patients may be at risk for withdrawal with prolonged use, adding to the complexity of sedation and agitation management in this patient population. Enteral α2 agents have the benefit of cost savings and ease of administration, thus playing a role in the ability to decrease intravenous sedative use and prevent dexmedetomidine withdrawal. Clonidine and guanfacine are the two most common enteral α2 agents utilized for this purpose, however, there is a paucity of evidence regarding the comparative benefit between the two agents. The decision to use one vs the other agent should be determined based on their differing pharmacology, pharmacokinetics, and side effect profile. The most effective dosing strategy for these agents is also unknown. Ultimately, more robust literature is required to determine enteral α2 agonists place in therapy. This narrative review evaluates the currently available literature on the use of α2 agonists in critically ill adults with an emphasis on sedation, delirium, and withdrawal. [ABSTRACT FROM AUTHOR]

Modulating role of circRNAs and microRNAs in neurobiological changes induced by drug exposure remains unclear. We examined alterations in some circRNAs and microRNAs in the striatum after morphine dependence and withdrawal and their associations with the changes in spatial working memory performance. Male Wistar rats were used in which 10 days morphine exposure induced dependence. Withdrawal effects were assessed 30 days after stopping morphine exposure. Spatial working memory was assessed using a Y maze test on days 1 and 10 of the drug exposure and 30 days after withdrawal. The gene and protein expression were assessed after dependence and withdrawal. The results revealed that 10 days morphine exposure impaired working memory, which partially reinstated after withdrawal. After 10 days morphine exposure, significant increases in Oprm1 gene and OPRM1 protein levels were detected, which persisted even after withdrawal. The expression of circOprm1 and miR-339-3p decreased in the morphine-dependent group, but they returned to normal levels after withdrawal. The expression of Tlr4 gene and TLR4 protein levels decreased after dependence. While Tlr4 mRNA levels returned to normal after withdrawal, TLR4 protein levels remained lower than the control group. In the morphine-dependent group, both Serpini1 and circSerpini expression significantly increased, but they restored after withdrawal. Expression of miR-181b-3p, miR-181b-5p, miR-181c-3p, and miR-181c-5p decreased after dependence, but they reinstated after withdrawal. It can be concluded that circOprm1 and circSerpini via regulating the OPRM1 and TLR4 expression in the striatum are associated with the neuroadaptation underlying spatial working memory after both morphine dependence and withdrawal. [ABSTRACT FROM AUTHOR]

Background and Objectives: Multiple evaluations of oxidative stress in individuals with substance use disorder show elevated levels compared to non-substance-abusing individuals. Information concerning antioxidant defense mechanisms in relation to alcohol and opioid dependence is variable and sometimes contradictory. The objective of the present investigation was to identify and compare several antioxidants in plasma during distinct phases of alcohol and opioid dependency (intoxication and withdrawal). Materials and Methods: This case study focuses on individuals with opioid and alcohol addiction. We recruited 80 participants (males aged 40 ± 10 years) and equally divided them into two categories: those with alcohol addiction and those with opioid addiction. A control group consisted of 20 healthy adults (males aged 35 ± 10 years). The spectrophotometric methods were used to quantify catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activity in plasma. Antioxidant values were analyzed between groups using pairwise Mann–Whitney tests. Results: During withdrawal from alcohol and opioids, catalase activity tends to decrease compared to intoxication. The overall activity of superoxide dismutase exhibited an increase during alcohol intoxication and withdrawal and a reduction during opioid withdrawal compared to the intoxication phase. Both alcohol and opioids reduced plasma GPx activity in withdrawal cases, although the extent of this decrease varied considerably. Conclusions: The study confirms the valuable impact of addiction on the organism's oxidative stress and reveals various behaviors of antioxidant defense enzymes during intoxication and withdrawal phases. [ABSTRACT FROM AUTHOR]

Introduction: Substance use disorders (SUDs) are a public health issue, with only some having FDA-approved indicated treatments and these having high attrition. Consequently, there has been interest in novel interventions (e.g. psychedelics that target 5-HT2A receptors) with some promising results. In this narrative review, we aim to focus on the role of the 5-HT2A receptors on the effectiveness of the treatment of SUDs. Areas covered: We evaluated the clinical evidence of the treatment of SUDs with non-psychedelic medications with a primary affinity for the 5-HT2A receptor. Expert opinion: The reviewed literature showed some positive effects on craving and abstinence but, overall, results were mixed. Comparison of this work with work on psychedelic agents suggests that mixed results are not unique to non-psychedelic agents. Both psychedelic and non-psychedelic drugs with 5-HT2A affinity are not exclusively selective for 5-HT2A receptors. The observation that most agents reviewed are 5-HT2A receptor antagonists instead of agonists and that psychedelics (typically 5-HT2A receptor agonists) may have more homogenous positive results gives more support to 5-HT2A receptor agonists as a promising group for treating SUDs. Mechanisms may target a common denominator across SUDs (e.g. chronic hypodopaminergic states). [ABSTRACT FROM AUTHOR]

Background: Dependence on gamma-hydroxybutyrate (GHB) is an emerging substance use disorder which can be life-threatening in overdose and withdrawal. The aim of this study was to describe rising GHB-related hospitalizations amidst the ongoing COVID-19 pandemic. Methods: A retrospective consecutive case series of adults admitted to hospitals in South Western Sydney Local Health District was identified with clinical coding of GHB-related disorder between March 20 2019 and March 20 2021. Morbidity outcomes and multivariable Kaplan–Meier survival analysis on length of hospital stay were described. Results: Sixty-nine of 84 included admissions, (82%) occurred in the 12 months following COVID-19 related border closure. Of 47 admissions for withdrawal, fifteen of 47 (32%) required intensive care, 6 (13%) intubation, 4 (9%) one-to-one ward observation, and 8 (17%) emergency calls for agitated delirium, fall, or seizure. Five cofactors were associated with longer hospital stay in the multivariable analysis: age 30 or older (p <.05), 6 months of regular GHB use (p <.01), and elective admission (p <.05), and diagnosis of psychosis rather than withdrawal (p <.05) or overdose (p <.001). Conclusions: Development of a validated GHB withdrawal severity scale based on these risk factors could help identify patients requiring close monitoring for complicated withdrawal and escalation of care. [ABSTRACT FROM AUTHOR]

The current opioid crisis has had an unprecedented public health impact. Approved medications for opioid use disorder (OUD) exist, yet their limitations indicate a need for innovative treatments. Limited preliminary clinical studies suggest specific psychedelics might aid OUD treatment, though most clinical evidence remains observational, with few controlled trials. This review aims to bridge the gap between preclinical findings and potential clinical applications, following PRISMA-ScR guidelines. Searches included MEDLINE, Embase, Scopus, and Web of Science, focusing on preclinical in vivo studies involving opioids and psychedelics in animals, excluding pain studies and those lacking control groups. Forty studies met criteria, covering both classic and non-classic psychedelics. Most studies showed that 18-methoxycoronaridine (18-MC), ibogaine, noribogaine, and ketamine could reduce opioid self-administration, alleviate withdrawal symptoms, and change conditioned place preference. However, seven studies (two on 2,5-dimethoxy-4-methylamphetamine (DOM), three on ibogaine, one on 18-MC, and one on ketamine) showed no improvement over controls. A methodological quality assessment rated most of the studies as having unclear quality. Interestingly, most preclinical studies are limited to iboga derivatives, which were effective, but these agents may have higher cardiovascular risk than other psychedelics under-explored to date. This review strengthens support for translational studies testing psychedelics as potential innovative targets for OUD. It also suggests clinical studies need to include a broader range of agents beyond iboga derivatives but can also explore several ongoing questions in the field, such as the mechanism of action behind the potential therapeutic effect, safety profiles, doses, and frequency of administrations needed. [ABSTRACT FROM AUTHOR]

Objectives: The feasibility of corticosteroid withdrawal (CW) for Takayasu arteritis (TAK) remains uncertain. Two autoantibodies (Abs) are identified against endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) in TAK, determining its three subgroups. This study aimed to evaluate CW using tocilizumab (TCZ) and its association with the Ab profile. Methods: This prospective study, lasted for 24 weeks, included patients with relapsed but stable TAK. Scheduled tapering of prednisolone (PSL) was performed with subcutaneous TCZ (CW at week 20). The primary endpoint was the difference in type A remission, defined by CW and the absence of inflammatory signs, according to the Ab profile at week 24. Results: Twenty patients were included and 18 patients with a mean PSL dose of 4.9 ± 2.8 mg/day were analysed. Anti-EPCR Ab-positive (E+), anti-SR-BI Ab-positive (S+), and double-negative (DN) groups included four (22.2%), eight (44.4%), and six (33.3%) patients, respectively. At week 24, the mean PSL dose was 2.0 ± 2.7 mg/day. Type A remission was observed in eight patients (44.4%), with significant differences based on the Ab profile: E+ (three patients, 75%), S+ (five patients, 62.5%), and DN (zero patients, 0%) (P=0.018). Besides, age, disease duration, PSL dose, type V arterial lesion, arterial dilation, and C-reactive protein >0.01 mg/dL were identified as risks for CW failure. Conclusion: CW using TCZ was achieved in 44.4% of patients with TAK relapse and was significantly higher in E+ and S+ patients. CW can be a feasible target, and the precise selection of patients is critical. [ABSTRACT FROM AUTHOR]

Background: Recruitment registries are maximally effective when registrants are retained to the point of referral. The Research Attitudes Questionnaire (RAQ) has previously been shown to predict research participation behaviors, including Alzheimer's disease clinical trial completion. Objective: To test the hypothesis that RAQ score is associated with retention behaviors in a local recruitment registry. Methods: Using data from the UC Irvine Consent-to-Contact Registry, a recruitment registry that enrolls adults 18 years and older, we used logistic regression to quantify the association of RAQ score and the odds of first-year non-renewal. Covariates included demographic variables, comorbidities, and recruitment source. In longitudinal analyses, we used discrete proportional hazards and Cox proportional hazards models to quantify the relationship between RAQ score and time to non-renewal and time to active withdrawal, respectively. Results: Among n = 4663 participants, we estimated that a 5-point higher baseline RAQ score was associated with a 15% lower odds of first-year non-renewal, after adjustment for potential confounding factors (OR: 0.85, 95% CI: (0.79, 0.92), p < 0.001). Older age and higher education were also associated with lower odds of non-renewal while Asian race, Hispanic ethnicity, and certain recruitment sources (e.g., doctor or friend referral) were associated with higher odds of non-renewal. Higher baseline RAQ and higher annually updated RAQ were both significantly associated with lower odds of non-renewal longitudinally. Age, education, and some recruitment sources, but not RAQ, were associated with active withdrawal. Conclusions: Opportunities exist to identify predictors of registry retention behaviors and possible targets for intervention to improve related outcomes. [ABSTRACT FROM AUTHOR]

Coitus interruptus – colloquially referred to as withdrawal – is an attempt at contraception wherein the penis is removed from the vagina prior to ejaculation, with ejaculation occurring somewhere outside the vagina. Although withdrawal can reduce the risk of pregnancy, it is less efficacious than methods such as consistent condom use and hormonal birth control. Consequently, it is of public health importance to identify sociocultural influences that either increase or decrease the likelihood of withdrawal as a contraceptive technique. Multiple content analyses have identified external ejaculation as common in popular pornography, yet no study appears to have assessed whether more frequent pornography consumption increases the likelihood of withdrawal behavior. Using national probability data, the present study examined whether pornography use and withdrawal were correlated among U.S. women aged 15–49. Women who consumed pornography more frequently were more likely to report using withdrawal as a contraceptive method than women who consumed pornography less frequently, but this association was moderated by perceptions of pornography’s utility and women’s marital status. Results are discussed through the lens of the sexual script acquisition, activation, application model (3AM) of sexual media socialization. [ABSTRACT FROM AUTHOR]

Purpose: Against the backdrop of the Russia-Ukraine conflict and ensuing industrial turmoil as well as the pressure of stakeholder sentiments, numerous U.S-based multinational B2B firms announced about their intent to withdraw from the Russian market. This study aims to probe the veracity of this form of corporate communication, exploring the corporate honesty effect by juxtaposing the stated withdrawal intentions against the actual scale of divestment. Methodology/approach: We identify 241 cases of response to the Russia-Ukraine conflict pertaining to U.S-based multinational B2B corporations. This includes 34 cases of no withdrawal (i.e., no communication) and 207 cases of announcements about the firm's intent to withdraw from Russia. For these cases, we calculate the actual scale of withdrawal (Actual Divestment Index) based on the data from Federal Tax Service of Russia and the Central Bank of the Russian Federation. Considering Actual Divestment Index as a fractional measure, we conduct fractional logit regression analysis, where the effect of the withdrawal communication on Actual Divestment Index is interpreted as the corporate honesty effect. Findings: Controlling for variables such as firm size, leverage, return on assets, institutional ownership, entry mode, and industry, the analysis reveals that the scope of intended withdrawal – reflected in the stages of no action, non-essential pullout, suspension, partial core, and full core withdrawal – is positively associated with the observed level of divestment. The findings further show that firms with larger corporate resources, higher profitability, and deeper local market exposure exhibit a greater level of corporate honesty. Research implications: This study builds on the MFHB framework (Cooper et al., 2023) that differentiates several distinct dimensions of corporate honesty. Our research applies these dimensions to formulate an operational definition of corporate honesty which emphasizes the fidelity to the firm's communicated intent, situationally activated in response to external pressures and emergent socio-political sentiments, in the context of established domestic/international business relationships. Also, we contribute to the current body of knowledge on corporate honesty by introducing a method of measuring the corporate honesty effect. Practical implications: Marketing managers of multinational B2B firms must endeavor to maintain the stakeholder perceptions of corporate legitimacy by constantly monitoring the level of corporate honesty effect, specifically during the time of war-induced disruptions and turmoil in B2B markets. Managers of B2B firms with larger resources, better profitability, and deeper market exposure can leverage their advantageous position to further highlight and promote their actual performance in this aspect to assuage the concerns and negative sentiments of stakeholders. Originality/value/contribution: This research contributes to theories of corporate honesty by contextualizing the concept of corporate honesty within the framework of communication-action congruence. This is done in relation to the strategic divestment communications and actions undertaken by B2B multinational firms in a market embroiled in moral turmoil during a geopolitical conflict. Our alternative operationalization of corporate honesty facilitates a quantifiable assessment of this construct, offering an alternative methodology to evaluate the integrity of corporate communications vis-à-vis actual organizational action in crisis contexts. Our findings about the boundary conditions of the corporate honesty effect contributes to a nuanced understanding of the phenomenon within the domain of sociopolitical corporate activism, ethical business practices, and international market dynamics. [ABSTRACT FROM AUTHOR]

Background and purpose: GABAergic neurons in mouse ventral tegmental area (VTA) exhibit elevated activity during withdrawal following chronic ethanol exposure. While increased glutamatergic input and decreased GABAA receptor sensitivity have been implicated, the impact of inhibitory signaling in VTA GABA neurons has not been fully addressed. Experimental approach: We used electrophysiological and ultrastructural approaches to assess the impact of chronic intermittent ethanol vapour exposure in mice on GABAergic transmission in VTA GABA neurons during withdrawal. We used CRISPR/Cas9 ablation to mimic a somatodendritic adaptation involving the GABAB receptor (GABABR) in ethanol‐naïve mice to investigate its impact on anxiety‐related behaviour. Key results: The frequency of spontaneous inhibitory postsynaptic currents was reduced in VTA GABA neurons following chronic ethanol treatment and this was reversed by GABABR inhibition, suggesting chronic ethanol strengthens the GABABR‐dependent suppression of GABAergic input to VTA GABA neurons. Similarly, paired‐pulse depression of GABAA receptor‐dependent responses evoked by optogenetic stimulation of nucleus accumbens inputs from ethanol‐treated mice was reversed by GABABR inhibition. Somatodendritic currents evoked in VTA GABA neurons by GABABR activation were reduced following ethanol exposure, attributable to the suppression of GIRK (Kir3) channel activity. Mimicking this adaptation enhanced anxiety‐related behaviour in ethanol‐naïve mice. Conclusions and implications: Chronic ethanol weakens the GABAergic regulation of VTA GABA neurons in mice via pre‐ and postsynaptic mechanisms, likely contributing to their elevated activity during withdrawal and expression of anxiety‐related behaviour. As anxiety can promote relapse during abstinence, interventions targeting VTA GABA neuron excitability could represent new therapeutic strategies for treatment of alcohol use disorder. [ABSTRACT FROM AUTHOR]

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Summary: Introduction: Obese rheumatoid arthritis (RA) patients often show reduced responses to traditional treatments, including TNF inhibitors (TNFi). Considering the different mechanisms of action it is important to evaluate the efficacy of tofacitinib in obese patients. This study aims to explore the impact of obesity on the drug survival of tofacitinib in RA patients. Material and methods: This retrospective cohort study included RA patients treated with tofacitinib. Patients were categorized into obese (BMI ≥ 30 kg/m2) and non-obese (BMI < 30 kg/m2) groups. The primary outcome was drug survival, assessed using Kaplan-Meier and logistic regression analyses. Results: The study comprised 80 RA patients, with 31 (39%) classified as obese. At the 12-month mark, the drug survival rate for tofacitinib was higher in the obese group (81%) compared to the non-obese group (59%). Contrary to univariable analysis, multivariate analysis did not identify obesity as a significant predictor of drug survival. Other variables including sex, hypertension, diabetes mellitus, and anti–cyclic citrullinated peptide (anti-CCP) positivity also showed no significant association with tofacitinib drug survival. Conclusion: The findings indicate that obesity does not alter the drug survival rate for tofacitinib among RA patients. Univariate analysis reported a potentially higher drug survival rate in obese patients; however, the lack of statistical significance in multivariate analysis and the study's retrospective nature necessitate further research to validate these observations and guide personalized therapeutic strategies for this population. [ABSTRACT FROM AUTHOR]

Cigarette smoking remains a leading cause of preventable disease and death worldwide. Due to the devastating negative health effects of smoking, many users attempt to quit, but few are successful in the long-term. Thus, there is a critical need for novel therapeutic approaches. In these investigations, we sought to examine whether cannabidiol (CBD) has the potential to be repurposed as a nicotine cessation therapeutic. In the first study, male and female mice were trained to respond for intravenous nicotine infusions at either a low or moderate nicotine dose and then were pretreated with CBD prior to their drug-taking session. We found that CBD produced a significant decrease in the number of nicotine rewards earned, and this effect was evidenced across CBD doses and with both the low and moderate levels of nicotine intake. These effects on drug intake were not due to general motor-related effects, since mice self-administering food pellets did not alter their behavior with CBD administration. The potential effects of CBD in mitigating nicotine withdrawal symptoms were then investigated. We found that CBD attenuated the somatic signs of nicotine withdrawal and prevented nicotine's hyperalgesia-inducing effects. Taken together, these results demonstrate that modulation of cannabinoid signaling may be a viable therapeutic option as a smoking cessation aid.

INTRODUCTION: An increased incidence of maternal opioid use disorder (OUD) and neonatal abstinence syndrome (NAS) has prompted recommendations supporting a dyadic approach to care for birthing persons and their infants. However, there are no consensus guidelines outlining how the dyad is clinically defined. METHODS: To examine how the opioid-exposed birthing person-infant dyad has been defined for purposes of data collection and research, a literature review applying the RAND/UCLA Appropriateness Method was conducted. RESULTS: The search yielded 320 abstracts, with 110 articles identified as having a dyadic focus. While no articles included a specific definition for the dyad, 33 (30%) contained a descriptive reference to the birthing person-infant dyad. Thematic analysis revealed eight recurring elements characteristic of the dyad: (1) engagement, (2) communication, (3) bonding, (4) attachment, (5) mutual responsiveness, (6) reciprocity, (7) synchrony, and (8) attunement. Integrating these elements revealed the interactional relationship between the opioid-exposed birthing person and infant as the foundational principle that defines the dyad. DISCUSSION: This definition shifts the focus of the opioid-exposed dyad from two individual patient populations to an interactional relationship that has broad applicability for clinical use, public health data collection, and research considerations.

ObjectiveMany persons with opioid use disorders (OUDs) have HIV disease and experience clinically significant stress after they enroll in abstinence-based treatment and undergo medically assisted withdrawal. We examined whether opioid withdrawal affects virologic control, inflammatory markers, cognition, and mood in persons with an OUD and HIV, and explored whether measures of withdrawal stress, such as activation of the HPA axis, contribute to alterations in immune function, cognition, and mood.Method and participantsStudy participants were 53 persons with HIV who were admitted for OUD treatment at the City Addiction Hospital in Saint Petersburg, Russian Federation. Participants were examined at admission, at the anticipated peak of withdrawal 3 to 7 days after the last day of a clonidine-based withdrawal process lasting 7 to 14 days, and 3 to 4 weeks after completing withdrawal. At these times, participants received medical exams and were evaluated for symptoms of withdrawal, as well as cognition and mood. Viral load, plasma cortisol, DHEA sulfate ester (DHEA-S), interleukin-6 (IL-6), and soluble CD14 (sCD14) were determined. Multivariable models examined the relationships between markers of HPA activation and the other parameters over time.ResultsHPA activation as indexed by cortisol/DHEA-S ratio increased during withdrawal, as did markers of immune activation, IL-6 and sCD14. There were no significant associations between viral load and indicators of HPA activation. In longitudinal analyses, higher cortisol/DHEA sulfate was related to worse cognition overall, and more mood disturbance. Increase in IL-6 was associated with worse cognitive performance on a learning task. There were no significant associations with sCD14.ConclusionsWorsening of cognition and measures of mood disturbance during withdrawal were associated with activation of the HPA axis and some measures of inflammation. Whether repeated episodes of opioid withdrawal have a cumulative impact on long-term HIV outcomes and neurocognition is a topic for further investigation.

Abstract Despite progress in smoking reduction in the past several decades, cigarette smoking remains a significant public health concern world-wide, with many smokers attempting but ultimately failing to maintain abstinence. However, little is known about how decision-making evolves in quitting smokers. Based on preregistered hypotheses and analysis plan ( https://osf.io/yq5th ), we examined the evolution of reinforcement learning (RL), a key component of decision-making, in smokers during acute and extended nicotine abstinence. In a longitudinal, within-subject design, we used a probabilistic reward task (PRT) to assess RL in twenty smokers who successfully refrained from smoking for at least 30 days. We evaluated changes in reward-based decision-making using signal-detection analysis and five RL models across three sessions during 30 days of nicotine abstinence. Contrary to our preregistered hypothesis, punishment sensitivity emerged as the only parameter that changed during smoking cessation. While it is plausible that some changes in task performance could be attributed to task repetition effects, we observed a clear impact of the Nicotine Withdrawal Syndrome (NWS) on RL, and a dynamic relationship between craving and reward and punishment sensitivity over time, suggesting a significant recalibration of cognitive processes during abstinence. In this context, the heightened sensitivity to negative outcomes observed at the last session (30 days after quitting) compared to the previous sessions, may be interpreted as a cognitive adaptation aimed at fostering long-term abstinence. While further studies are needed to clarify the mechanisms underlying punishment sensitivity during nicotine abstinence, these results highlight the need for personalized treatment approaches tailored to individual needs.

Abstract Taking the perspective of career choice as a lifelong, iterative, constructive, and agentic process, the present study focuses on the development of vocational aspirations of nursing trainees; that is, thoughts about a long-term perspective in nursing (i.e., persistence), ideas of finishing the training but changing into another profession after some time (i.e., withdrawal), and decisions to terminate the training before completing the programme through a final examination (i.e., dropout). In order to generate detailed insights about the dynamics behind the development of such aspirations during the initial training phase, a qualitative, longitudinal, within-subject study design based on grounded theory was employed. The results mainly show that social interactions with more experienced nurses, practical work experiences, encounters with environments that are either conducive to learning or not, the satisfaction of different needs (e.g., autonomy, competence, belonging, sense of meaningfulness), as well as the associated feelings of well-being affect how vocational aspirations develop over the first year of training. In addition, the study identifies four different patterns of how trainees typically oscillate between thoughts of staying in nursing and leaving the profession in the short or long run: (a) arriving and wanting to stay, (b) staying as a transitional passage, (c) seeking to stay, and (d) exiting as a knee-jerk reaction. The patterns present evidence of a variety of approaches regarding how trainees deal with certain experiences during their training and how the combination of experiences might affect young professionals’ subsequent career choices.

Abstract Background Chronic cigarette smokers report withdrawal symptomology, including affective dysfunction and cognitive deficits. While there are studies demonstrating sex specific withdrawal symptomology in nicotine-dependent individuals, literature examining the underlying biological mediators of this is scant and not in complete agreement. Therefore, in this study, we evaluated the sex specific effects of nicotine and withdrawal on contextual fear memory, a hippocampally dependent aspect of cognition that is disrupted in nicotine withdrawal. Methods Male and female B6/129F1 mice (8–13 weeks old) were used in all experiments. For the acute nicotine experiment, mice received intraperitoneal saline or nicotine (0.5 mg/kg) prior to contextual fear conditioning and test. For the chronic nicotine experiment, mice received nicotine (18 mg/kg/day) or saline for 11 days, then underwent contextual fear conditioning and test. Following the test, mice underwent minipump removal to elicit withdrawal or sham surgery, followed by the fear extinction assay. Bulk cortical tissue was used to determine nicotinic acetylcholine receptor levels via single point [3H]Epibatidine binding assay. Gene expression levels in the dorsal and ventral hippocampus were quantified via RT-PCR. Results We found that female mice had a stronger expression of contextual fear memory than their male counterparts. Further, following acute nicotine treatment, male, but not female, subjects demonstrated augmented contextual fear memory expression. In contrast, no significant effects of chronic nicotine treatment on fear conditioning were observed in either sex. When examining extinction of fear learning, we observed that female mice withdrawn from nicotine displayed impaired extinction learning, but no effect was observed in males. Nicotine withdrawal caused similar suppression of fosb, cfos, and bdnf, our proxy for neuronal activation and plasticity changes, in the dorsal and ventral hippocampus of both sexes. Additionally, we found that ventral hippocampus erbb4 expression, a gene implicated in smoking cessation outcomes, was elevated in both sexes following nicotine withdrawal. Conclusions Despite the similar impacts of nicotine withdrawal on gene expression levels, fosb, cfos, bdnf and erbb4 levels in the ventral hippocampus were predictive of delays in female extinction learning alone. This suggests sex specific dysfunction in hippocampal circuitry may contribute to female specific nicotine withdrawal induced deficits in extinction learning.

Despite progress in smoking reduction in the past several decades, cigarette smoking remains a significant public health concern world-wide, with many smokers attempting but ultimately failing to maintain abstinence. However, little is known about how decision-making evolves in quitting smokers. Based on preregistered hypotheses and analysis plan (https://osf.io/yq5th), we examined the evolution of reinforcement learning (RL), a key component of decision-making, in smokers during acute and extended nicotine abstinence. In a longitudinal, within-subject design, we used a probabilistic reward task (PRT) to assess RL in twenty smokers who successfully refrained from smoking for at least 30 days. We evaluated changes in reward-based decision-making using signal-detection analysis and five RL models across three sessions during 30 days of nicotine abstinence. Contrary to our preregistered hypothesis, punishment sensitivity emerged as the only parameter that changed during smoking cessation. While it is plausible that some changes in task performance could be attributed to task repetition effects, we observed a clear impact of the Nicotine Withdrawal Syndrome (NWS) on RL, and a dynamic relationship between craving and reward and punishment sensitivity over time, suggesting a significant recalibration of cognitive processes during abstinence. In this context, the heightened sensitivity to negative outcomes observed at the last session (30 days after quitting) compared to the previous sessions, may be interpreted as a cognitive adaptation aimed at fostering long-term abstinence. While further studies are needed to clarify the mechanisms underlying punishment sensitivity during nicotine abstinence, these results highlight the need for personalized treatment approaches tailored to individual needs. [ABSTRACT FROM AUTHOR]

The N-methyl-D-aspartate (NMDA) glutamate receptor is a major target of ethanol, and it is implicated in learning and memory formation, and other cognitive functions. Glycine acts as a co-agonist for this receptor. We examined whether Org24598, a selective inhibitor of glycine transporter1 (GlyT1), affects ethanol withdrawal-induced deficits in recognition memory (Novel Object Recognition (NOR) task) and spatial memory (Barnes Maze (BM) task) in rats, and whether the NMDA receptor glycine site participates in this phenomenon. Male Wistar rats were habituated to NOR or BM tasks, and then received binge-like intragastric ethanol administration (5 days, 5 g/kg). After ethanol withdrawal, Org24598 (0.1, 0.3, and 0.6 mg/kg) was administered 30 min before NOR (day 10 of withdrawal) or the reversal learning phase of BM (day 11–13 of withdrawal) task. The expression of GluN1 and GluN2B subunits of NMDA receptors were measured in the perirhinal cortex (PRC) and hippocampus (HIP) after termination of NOR. In the BM task, a glycine antagonist, L-701,324 (5 mg/kg), was administered 30 min before Org24598 to confirm the involvement of the NMDA receptor glycine site in the effects of Org24598. Our study showed that binge-like ethanol administration induced recognition and spatial memory impairments after withdrawal in rats. Additionally, an up-regulation of GluN1 and GluN2B subunits of the NMDA receptor was observed in the HIP and PRC on day 11 of abstinence. Org24598 ameliorated memory loss and normalized the expression of these subunits. L-701,324 reversed the effect of Org24598. Thus, NMDA receptor glycine sites are important in ethanol withdrawal-induced memory impairments. [ABSTRACT FROM AUTHOR]

Background Materials and methods Results Conclusion The present study aims to assess the therapeutic potential of vitamin C (Vit C) on anxiety‐ and depressive‐like behavior induced by abstinence from chronic nicotine‐ethanol co‐exposure in adolescent male rats.Adolescent male rats were divided into seven experimental groups with ten rats as follows: 1) vehicle, 2) Nicotine (Nic)‐Ethanol (Eth): received Nic (2 mg/kg) and Eth (20%) in drinking water from 21 to 42 days of age, 3–5) Nic‐Eth‐Vit C 100/200/400: received Nic and Eth from 21 to 42 days of age and received Vit C 100/200/400 mg/kg from 43 to 63 days of age, 6) Nic‐Eth‐Bupropion (Bup)‐ Naloxone (Nal): received Nic and Eth from 21 to 42 days of age and received Bup and Nal from 43 to 63 days of age, and 7) Vit C 400 mg/kg: received Vit C 400 mg/kg from 43 to 63 days of age. Behavioral assessments were done by elevated plus maze (EPM), forced swimming test (FST), marble burring test (MBT), and open field tests (OFT). Furthermore, specific biochemical variables associated with oxidative, inflammatory, and serotonergic profiles were quantified.According to the obtained results, Nic and Eth induced anxiety and depression in treated rats. We showed that two higher doses of Vit C increases the active struggling time in FST and decreases both the time spent in the peripheral zone of OFT and the time spent in the closed arms of EPM. In addition, animals treated by Vit C buried less number of marbles in MBT compared to their control counterparts. Nic and Eth induced oxidative stress and inflammation in cortical tissues of treated rats. Biochemical parameters were improved in the Nic‐Eth group receiving Vit C 200/400 mg/kg and Bup‐Nal through establishing a balance between oxidant/anti‐oxidant and inflammatory/anti‐inflammatory mediators. In addition, serotonin level was increased, while Monoamine oxidase (MAO) activity was notably decreased.The present findings support the beneficial effect of Vit C on anxiety‐ and depressive‐like behavior induced by Nic‐Eth withdrawal through various mechanisms such as the promotion of antioxidant defense, suppression of inflammatory mediators, and enhancement of serotoninergic function. [ABSTRACT FROM AUTHOR]

Personality disorders (PD) are prevalent co-morbid conditions among addicted individuals. Our study aimed to determine whether long-term, continuous use of benzodiazepines (over a year) leads to the development of symptoms of dependence considering the presence or absence of personality disorders. The group consisted of 78 benzodiazepine users who used benzodiazepine as a monotherapy for at least 1 year before a screening. Patients completed a group of questionnaires: a semi-structured questionnaire for sociodemographic data as well as for basic data on the use of benzodiazepines, Wisconsin Personality Inventory, and Benzodiazepine Dependence Self-Report Questionnaire. The group was divided into two subgroups: the group of subjects with personality disorders (60.26%) and those without personality disorders (39.74%). These two groups were mutually compared concerning: (a) correlates of benzodiazepine dependence (problematic use of benzodiazepines, preoccupation with benzodiazepines, lack of compliance, and withdrawal syndrome) and (b) intensity of benzodiazepine dependence. In the whole group, approximately 70% of subjects had positive indicators for physical dependence (lack of compliance due to a rise of tolerance in 73.08% and withdrawal in 70.51% of subjects). The psychological dependence indicator (preoccupation with benzodiazepines) was positive in 94.87% of subjects, as well as for social aspects of dependence (problematic use of BDZs) in 93.59%. The total score, or intensity of benzodiazepine dependence, was statistically higher in the group with personality disorder. Patients with a personality disorder had more frequent and more intensive preoccupation with benzodiazepine and lack of compliance. Co-occurrence of two or more personality disorders increases the intensity of preoccupation with a benzodiazepine. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the demographic data and resolved-relapse rates in clinical follow-up of patients whose antiseizure medications (ASM) were discontinued after a minimum of 2 years of seizure freedom. Methods: The files of 1985 patients followed in the epilepsy outpatient clinic were evaluated retrospectively. The inclusion criteria for patients were between 18 and 65 years old, followed up at an epilepsy outpatient clinic, and having discontinued ASM after at least 2 years of seizure freedom under the supervision of a neurologist. Results: A total of 56 patients were included in the study. The age of onset of seizures was 13.9±10.04 years, the age of onset of ASM was 15.87±9.69 years, and the age of quitting ASM was 24.58±11.54 years. The patients had a mean seizure-free period of 64.46±32.27 months before drug discontinuation and 43.73±38.87 months after drug discontinuation. The EEGs of 49 patients were normal in the EEGs performed after drug discontinuation, and seven patients had epileptiform discharges. Relapse was observed in 23.2% of patients after drug discontinuation. It was observed that 69% of the recurrences in 13 patients occurred within the first 2 months. Conclusion: Although seizure recurrence probability is highest during the first 2 months after ASM discontinuation, it is still possible 6 years later in adults with inactive epilepsy. The time window without seizures before ASM discontinuation and follow-up EEGs afterwards may help in the prediction of seizure recurrence. [ABSTRACT FROM AUTHOR]

Smoking rates in schizophrenia are exceptionally high; however, cessation rates remain low with limited research on effective interventions. A critical component of intervention development is identifying the effects of abstinence that are most salient and therefore may contribute to lapse and relapse. We conducted a systematic review and meta-analysis of controlled laboratory studies investigating acute smoking abstinence effects among people with schizophrenia and schizoaffective disorder. This review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. OVID (MEDLINE, EMBASE, PsycINFO) and PubMed databases were searched from inception until November 2023. We identified (k = 16) articles meeting inclusion criteria; all assessed smoking abstinence (ranging 2–120 h). Acute abstinence resulted in large increases in reward-oriented craving and moderate increases in relief-oriented craving; these effects were greater in studies with longer abstinence duration (high certainty). We also observed significant increases in negative affect and global withdrawal symptoms, as well as memory disruption (moderate certainty). Qualitative synthesis suggests restlessness, irritability, anxiety, and visuospatial working memory may be additionally impacted. Findings with respect to negative symptoms and movement were mixed. Reward-oriented craving may constitute a key target of smoking cessation interventions for people with schizophrenia. In addition, identification of pharmacological and psychosocial interventions that address abstinence-induced changes in relief-oriented craving, memory, negative affect, restlessness, irritability, and anxiety may strengthen treatment outcomes. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) poses a significant public health challenge. Individuals with AUD engage in chronic and excessive alcohol consumption, leading to cycles of intoxication, withdrawal, and craving behaviors. This review explores the involvement of the cortical amygdala (CoA), a cortical brain region that has primarily been examined in relation to olfactory behavior, in the expression of alcohol dependence and excessive alcohol drinking. While extensive research has identified the involvement of numerous brain regions in AUD, the CoA has emerged as a relatively understudied yet promising candidate for future study. The CoA plays a vital role in rewarding and aversive signaling and olfactory-related behaviors and has recently been shown to be involved in alcohol-dependent drinking in mice. The CoA projects directly to brain regions that are critically important for AUD, such as the central amygdala, bed nucleus of the stria terminalis, and basolateral amygdala. These projections may convey key modulatory signaling that drives excessive alcohol drinking in alcohol-dependent subjects. This review summarizes existing knowledge on the structure and connectivity of the CoA and its potential involvement in AUD. Understanding the contribution of this region to excessive drinking behavior could offer novel insights into the etiology of AUD and potential therapeutic targets. • The cortical amygdala is involved in alcohol-dependent drinking. • The cortical amygdala connects to key brain regions involved in alcohol use disorder. Increased the cortical amygdala activity during alcohol withdrawal in dependent subjects may enhance glutamatergic signaling to the central amygdala, bed nucleus of the stria terminalis and basolateral amygdala. [ABSTRACT FROM AUTHOR]

Objective: Antipsychotics remain the first‐line treatment for people diagnosed with psychotic disorders despite adverse effects which lead many people to stop their medication. Many stop without the support of the prescriber, who may fear relapse. The objective of this study is to better understand the process of withdrawal from antipsychotics, from the perspective of people taking antipsychotics. Design: Online survey. Methods: An international online survey elicited quantitative responses about pre‐withdrawal planning (560) and qualitative responses about what was helpful and unhelpful when withdrawing from antipsychotics (443). Responses came from users of antipsychotics in 29 countries. Results: Forty‐seven per cent did not consult their psychiatrist before discontinuing. Only 40% made preparations, most commonly making a plan, gathering information and informing family. The most frequently reported helpful factors were focussing on the benefits of getting off the drugs (including ending adverse effects and feeling more alive), information about withdrawal symptoms and how to withdraw safely, withdrawing slowly, and support from psychologists, counsellors and psychotherapists. The most common unhelpful factor was the psychiatrist/doctor, largely because of their lack of knowledge, refusal to support the patient's wishes and the threat or use of coercion. Conclusions: Evidence‐based, respectful, collaborative responses to patients' concerns about adverse effects and desires to withdraw would probably reduce relapse rates and improve long‐term outcomes. It would definitely help end pervasive breaching of the principle of informed consent and human rights legislation. [ABSTRACT FROM AUTHOR]

Objective Management of neonatal abstinence syndrome includes nonpharmacological interventions, but their effectiveness may not be verified before implemented. The objective of this study is to evaluate the effectiveness of a type of bassinet in the treatment of infants with neonatal abstinence syndrome. Study Design This is a retrospective observational cohort study. Study setting involved a 24-bed open-bay Level III neonatal intensive care unit located in a metropolitan academic trauma facility. Participant inclusion criteria involved prenatally opioid-exposed infants ≥ 35 weeks with confirmed maternal opioid urine toxicology, required pharmacological treatment for withdrawal symptoms, and were admitted to the neonatal intensive care unit. Three subsets of study participants were analyzed over three different time periods: Group 1 were infants admitted during 2019 without nonpharmacological intervention, Group 2 who were admitted from September 2021 to February 2022 and received nonpharmacological interventions, and Group 3 included those admitted from February 2022 to March 2023 who received the same interventions as Group 2 but were managed in bassinets being used in other local facilities for neonatal abstinence syndrome. Results Group 3 had significant increases in length of stay compared with Group 1 (p = 0.006) and Group 2 (p = 0.013). Group 3 had a significantly greater length of treatment than Group 1 (p = 0.041) and a significantly higher total mg/kg morphine exposure than Group 1 (p = 0.006). Conclusion Addition of the bassinet for nonpharmacological management of infants with neonatal abstinence syndrome appeared to prolong length of stay, length of treatment, and increase total mg/kg morphine exposure. As a retrospective nonrandomized study, weakness of low certainty of causality is of concern but findings strongly warrant further research before devices such as the bassinet used in this study are adopted for routine neonatal abstinence syndrome care. Key Points Special bassinets are promoted to enhance sleep and decrease agitation. Such bassinets may assist infants undergoing drug withdrawal. Study of the bassinet failed to show benefit to this population. [ABSTRACT FROM AUTHOR]

Background: Social impairment has long been associated with psychosis, but recently a more nuanced understanding of how relationships are impacted by psychosis is emerging, taking into account both positive social changes (e.g. improved relationships, increased empathy for others) as well as challenges (e.g. stigma, shame). Methods: Ten participants were recruited from two early intervention services to participate in semi-structured interviews pertaining to their lived experience of psychosis. Thematic analysis was conducted on data related to social experiences during and after psychosis. Results: Participants reported a wide spectrum of experiences. Social withdrawal was common and sometimes enacted to protect oneself or others. Some participants reported feelings of confusion, shame, and guilt, resulting in internalized stigma and making it difficult to navigate relationships, especially after an experience of psychosis. Many participants reported positive social changes, including new, more meaningful, and closer relationships. Discussion: Recovery and adaptation following psychosis is not a linear process, and signs of both distress and growth may occur in parallel. Likewise, social withdrawal and connection may take place simultaneously or successively. More attention should be paid in both research and practice to the myriad ways in which psychosis impacts relationships and how this matters to service users. [ABSTRACT FROM AUTHOR]

Background: Phenobarbital (PHB) has been shown to be an effective treatment of alcohol withdrawal syndrome (AWS), with multiple dosing strategies used (e.g., single-dose and symptom-triggered). Studies have often used tapered doses, typically following a front-loaded dose, despite PHB's long half-life which should lead to an ability to auto-taper. Objective: The purpose of this study was to compare clinical outcomes associated with two PHB dosing strategies (taper [T], no taper [NT]) for AWS. Methods: This retrospective cohort study compared adult patients admitted to the ICU from October 2017 to May 2019 who received an initial loading dose of PHB for AWS. The use of PHB was at the discretion of the clinician per our institutional guidelines. Prior to November 2018, patients were prescribed a PHB taper, while after this period, the taper was no longer recommended. The primary outcome was the proportion of patients requiring rescue PHB or adjunctive medications for AWS. Secondary outcomes included number of adjunctive agents used, prevalence of severe manifestations of AWS, ICU and hospital lengths of stay, and incidence of potentially significant drug interactions. Results: A total of 172 patients were included (T: n = 81, NT: n = 91). Baseline characteristics were similar between groups, including history of severe AWS and cumulative benzodiazepine dose pre-PHB. There was no difference in the primary outcome between groups (T: 70.4% vs NT: 59.3%, P = 0.152). The median number of adjunctive agents per patient, severe manifestations, and ICU and hospital length of stay did not differ between groups. Twenty-five patients (14.5%) had potentially significant drug interactions. Conclusion and Relevance: The use of a PHB loading dose without a taper may be comparable to a taper strategy on clinical outcomes. Prospective studies are needed to further delineate the optimal dose of PHB for AWS. [ABSTRACT FROM AUTHOR]