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Background: Cocaine use disorder (CUD) has significant consequences and there remain no FDA-approved pharmacotherapies. Ondansetron is an indirect dopaminergic modulator that has shown efficacy in alcohol use disorder, particularly in phenotypic and genotypic subgroups, and was found to be efficacious in a pilot dose-finding trial for CUD., Methods: One-hundred eight (108) adults with CUD were randomized to ondansetron 4 mg twice daily or placebo for 9 weeks and assessed up to thrice weekly to evaluate self-reported cocaine use and urine benzoylecgonine. Participants received cognitive-behavioral therapy and brief behavioral compliance enhancement therapy. Consenting participants (N = 79) provided blood samples for exploratory pharmacogenetic analyses., Results: Participants in both arms reduced cocaine use over time, but there was no statistically significant difference on percentage of cocaine-free days (PCFD; p = 0.972) or percentage of cocaine-free urine samples (PCFU; p = 0.909). Participants with early-onset CUD had greater improvement regardless of study arm (p = 0.002). Post hoc pharmacogenetic analyses demonstrated an interaction effect between treatment and rs1176713 SNP on PCFU in the total sample (p = 0.040) and African ancestry subset (p = 0.03). Constipation, fatigue, and somnolence were more common among ondansetron-treated participants (Fisher exact p < 0.05). Those who developed constipation were mostly rs1176713:GG carriers (Fisher exact p = 0.029)., Conclusions: Ondansetron did not demonstrate efficacy in the treatment of CUD. However, these preliminary results suggest a genotype-based variance in response to ondansetron in African ancestry individuals with CUD. Further studies are needed to validate findings for developing a personalized genomic approach for CUD treatment in racially and ethnically diverse populations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Buprenorphine prescriptions have increased dramatically within the United States, whereas methadone continues to be used widely. We investigated the trends and characteristics of buprenorphine and methadone exposures in the pediatric population., Methods: We identified pediatric exposures to buprenorphine and methadone using the National Poison Data System from 2013 to 2016. We descriptively assessed characteristics of the exposures. Trends in exposures were evaluated using generalized linear mixed models., Results: Pediatric buprenorphine exposures increased from 2013 (1097) to 2016 (1226) while methadone calls decreased (486 to 396). After adjusting for the random effects of the geographical region, the mean number of pediatric buprenorphine exposures (per 100,000 pediatric population) increased from 1.3 to 1.5 (P = .05). Conversely, the mean number of methadone exposures decreased from 0.6 to 0.4 (P = .03). Children aged ≤3 years constituted the highest percentage of both exposures. Unintentional exposures accounted for most of the buprenorphine (86.9%) and methadone (62.4%) exposures. Major clinical effects were demonstrated in 2.3% of buprenorphine exposures and were more frequent with methadone (13%). West Virginia and Maryland demonstrated the highest incidence of buprenorphine and methadone exposures, respectively., Conclusions: Pediatric buprenorphine exposures increased but demonstrated less severe effects compared to methadone exposures, which decreased during the study period., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Gender-related alcohol and drug abuse problems are related not only to biologic differences but also to social and environment factors, all of which can influence the clinical presentation, consequences of use, and treatment approaches. The number of women becoming addicted to alcohol or drugs of abuse has significantly increased with women becoming the fastest-growing group of substance abusers in the United States. Given that women experience a more rapid progression of their addiction than men, it is important that we understand and address the differences to help develop prevention and treatment programs that are tailored for women, incorporating trauma assessment and management, comorbidities, financial independence, pregnancy, and child care., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: This study aims to evaluate the trends and risk factors of severe buprenorphine outcomes (SBO) reported to the U.S. Poison Centers (PCs)., Methods: We queried the National Poison Data System for exposures to buprenorphine from 2011 to 2016. SBO cases were defined as exposures that resulted in either a death or major clinical outcomes. Trends were tested using Poisson regression. Characteristics of the exposures were descriptively assessed. Logistic regression was used to evaluate the risk factors of SBO., Results: SBO cases (967) reported to the PCs increased by 66.6% during this period (114-190, p < 0.001). While adults between 20 and 39 years were more frequent in the SBO group (50.4%) compared to the non-SBO group (38.7%), cases under 6 years (29.6% vs 13.8%) were more common among the non-SBO group. Intentional abuse (20.1% vs 24.9%) and suspected suicides (13.7% vs 37.5%) were significantly higher among the SBO group. Multisubstance exposures were more frequent among the SBO cases (36.4% vs 71.4%). SBO risk increased with age, with cases above 60 years (AOR: 1.66, 95% CI: 1.14-2.42) demonstrating significantly increased odds. Suspected suicide (AOR: 1.87, 95% CI: 1.53-2.28) and abuse (AOR: 1.40, 95% CI: 1.13-1.73) cases were more likely to result in a SBO. Multisubstance exposures significantly increased the risk of a SBO., Conclusions: This study reflected an increase in the cases of SBO paralleling the rise in the buprenorphine prescriptions. Age, reasons for exposure and multi-substance exposures significantly increased the risk of SBO., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: This study aimed to develop a predictive model to quantify the risk of student harmful drinking associated with emergency department (ED) visits and/or campus-wide incidents reported to campus authorities in a U.S. public university., Methods: Six-year (2010/11-2015/16) student enrollment data were linked to subsequent harmful drinking events defined as either alcohol intoxication associated with ED visits or alcohol-related incidents reported to authorities within 1 year following the annual (index) enrollment. Multivariable logistic regression analysis was used to develop a risk predictive model based on the first 3-year student cohort (n = 93,289), which was then validated in the following 3-year student cohort (n = 85,876)., Results: A total of 2609 students in the derivation cohort and 2617 students in the validation cohort had at least 1 harmful drinking event within 1 year following the index enrollment, providing an incidence of 2.8% and 3.1%, respectively. Student demographics (gender, age, ethnicity, parental tax dependency), academic level, Greek life member, transfer students, first-time enrolled students, having been diagnosed with depression or injury, and violence involvement were statistically significant predictors. C-statistics of the model were 0.86 in both cohorts, with excellent calibration and no evidence of over- or under-prediction observed from calibration plots., Conclusions: By linking routinely collected student data, a robust risk predictive model was developed and validated to quantify absolute risk of harmful drinking for every student. This model can provide a useful tool for clinicians or health educators to make real time decision to plan target interventions for students at elevated risk., (Copyright © 2019. Published by Elsevier B.V.)

Background: To examine the trends in incidence and socio-demographic, organizational, academic, and clinical risk markers of student alcohol intoxication associated with emergency department (ED) visits., Methods: Student admission data from 2009 to 2015 were linked to primary healthcare data and subsequent ED visits with alcohol intoxication identified using ICD-9 codes within one year following the first (index) enrollment each year. Incidence rate per 10,000 person-years was calculated. Cox proportional hazard regression provided adjusted hazard ratios (HR) (95 % CIs) for the association between student characteristics and subsequent ED visits with alcohol intoxication., Results: Of 177,128 students aged 16-49 enrolled, 889 had at least one ED visit with alcohol intoxication, resulting in an incidence rate of 59/10,000 person-years. Incidence increased linearly from 45/10,000 person-years in 2009-10 to 71/10,000 person-years in the 2014-15 academic year (p < 0.001). HRs (95%CIs) of student characteristics associated with this outcome were: males (versus females): 1.38 (1.21-1.58); below 20 years of age (versus 25-30 years): 3.36 (1.99-5.65); Hispanic (versus Asian) students: 1.61 (1.16-2.25); parental tax dependency: 1.49 (1.16-1.91); Greek life member: 1.96 (1.69-2.26); member of an athletic team: 0.51 (0.36-0.72); undergraduate (versus graduate) students: 2.65 (1.88-3.74). Past year alcohol use or having been diagnosed with depression or anxiety were also significant predictors. Adjustments for campus-related factors strongly attenuated the associations between student socio-demographic characteristics with this outcome., Conclusions: Linking student admission data with ED clinical data can help monitor student alcohol intoxication associated with ED visits and identify student groups at higher risk who subsequently can be targeted for intervention efforts., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Few studies have explored the epidemiology of students presenting to the emergency department (ED) as a consequence of hazardous drinking. This study examined differentials and trends in ED visits following alcohol intoxication and co-occurring conditions among students presenting to a major U.S. university health system., Methods: The ED electronic medical records from academic years 2010-2015 were queried for student visits and their records were linked to the university's student admission datasets. Student alcohol-related visits were identified based on ICD-9 codes. Student characteristics and trends in the rate of alcohol intoxication per 100 ED student visits were analyzed. A random sample of 600 student clinical records were reviewed to validate diagnostic codes., Results: There were 9616 student ED visits (48% males) to the ED of which 1001 (10.4%) visits involved alcohol intoxication. Two thirds of ED visits with alcohol intoxication had a co-occurring diagnosis, with injuries (24%) being the most common condition. The rate of alcohol intoxication varied greatly by student demographics and campus-related factors. There was a linear increase in the rate of alcohol intoxication from 7.9% in 2009-10 to 12.3% in 2014-15 (p<0.01). The increase was greater among female students, students below 20 years of age, Asian students, and student athletes. In the sample reviewed, only two thirds of ED visits with alcohol intoxication were recorded by diagnostic codes., Conclusion: The rate of ED visits following alcohol intoxication varied by student demographic characteristics and campus-related factors with a rising trend over the study period., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: As reported previously, 140 methamphetamine-dependent participants at eight medical centers in the U.S. were assigned randomly to receive topiramate (N=69) or placebo (N=71) in a 13-week clinical trial. The study found that topiramate did not appear to reduce methamphetamine use significantly for the primary outcome (i.e., weekly abstinence from methamphetamine in weeks 6-12). Given that the treatment responses varied considerably among subjects, the objective of this study was to identify the heterogeneous treatment effect of topiramate and determine whether topiramate could reduce methamphetamine use effectively in a subgroup of subjects., Methods: Latent variable analysis was used for the primary and secondary outcomes during weeks 6-12 and 1-12, adjusting for age, sex, and ethnicity., Results: Our analysis of the primary outcome identified 30 subjects as responders, who either reduced methamphetamine use consistently over time or achieved abstinence. Moreover, topiramate recipients had a significantly steeper slope in methamphetamine reduction and accelerated to abstinence faster than placebo recipients. For the secondary outcomes in weeks 6-12, we identified 40 subjects as responders (who had significant reductions in methamphetamine use) and 65 as non-responders; topiramate recipients were more than twice as likely as placebo recipients to be responders (odds ratio=2.67; p=0.019). Separate analyses of the outcomes during weeks 1-12 yielded similar results., Conclusions: Methamphetamine users appear to respond to topiramate treatment differentially. Our findings show an effect of topiramate on the increasing trend of abstinence from methamphetamine, suggesting that a tailored intervention strategy is needed for treating methamphetamine addiction., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Prior studies have demonstrated inefficacy among dopamine receptor antagonists for treating cocaine dependence. An alternative approach would be to investigate the ability of indirect inhibitors of cortico-mesolimbic dopamine release, such as the 5-HT(3) receptor antagonist ondansetron, to reduce cocaine's reinforcing effects. We hypothesized that ondansetron might be more efficacious than placebo at reducing cocaine intake and promoting abstinence in cocaine-dependent individuals. In a pilot randomized, double-blind, 10-week controlled trial, 63 treatment-seeking, cocaine-dependent men and women received ondansetron (0.25 mg, 1.0 mg, or 4.0 mg twice daily) or placebo. Up to three times per week, participants were assessed on several measures of cocaine use, including urine benzoylecgonine. Cognitive behavioral therapy was administered weekly. Ondansetron was well tolerated, causing no serious adverse events. The ondansetron 4.0 mg group had the lowest dropout rate among all treatment groups and a greater rate of improvement in percentage of participants with a cocaine-free week compared with the placebo group (p = 0.02), whereas the ondansetron 1.0 mg group had a lower rate of improvement in percentage of weekly mean non-use days than did placebo recipients (p = 0.04). These results suggest the possibility of a non-linear dose-response function, with evidence supporting efficacy for the 4.0 mg group.

Background: Topiramate, a sulphamate fructopyranose derivative, might antagonise alcohol's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function. We aimed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence., Methods: We did a double-blind randomised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence. Of these 150 individuals, 75 were assigned to receive topiramate (escalating dose of 25-300 mg per day) and 75 had placebo as an adjunct to weekly standardised medication compliance management. Primary efficacy variables were: self-reported drinking (drinks per day, drinks per drinking day, percentage of heavy drinking days, percentage of days abstinent) and plasma gamma-glutamyl transferase, an objective index of alcohol consumption. The secondary efficacy variable was self-reported craving., Findings: At study end, participants on topiramate, compared with those on placebo, had 2.88 (95% CI -4.50 to -1.27) fewer drinks per day (p=0.0006), 3.10 (-4.88 to -1.31) fewer drinks per drinking day (p=0.0009), 27.6% fewer heavy drinking days (p=0.0003), 26.2% more days abstinent (p=0.0003), and a log plasma gamma-glutamyl transferase ratio of 0.07 (-0.11 to -0.02) less (p=0.0046). Topiramate-induced differences in craving were also significantly greater than those of placebo, of similar magnitude to the self-reported drinking changes, and highly correlated with them., Interpretation: Topiramate (up to 300 mg per day) is more efficacious than placebo as an adjunct to standardised medication compliance management in treatment of alcohol dependence.