Modafinil Does Not Reduce Cocaine Use in Methadone-Maintained Individuals.

Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.

Does altitude increase the risk of traumatic aortic injuries? A retrospective cohort study among six level I trauma centers in the United States.

BACKGROUND: Traumatic aortic injuries (TAIs) are rare but are associated with a high mortality. Prior studies have shown skiers and pilots, whose injuries occur at high altitudes, are at an increased risk for a TAI. The purpose of this study was to examine the effect of altitude on the incidence of TAIs across all causes of injury. METHODS: This retrospective cohort study at six Level I trauma centers (8/1/2016-1/1/2020) included adult blunt trauma patients with a chest or abdomen injury. High altitude injuries (> 5000 ft.) were compared to low altitude injuries (≤ 5000 ft.). The primary outcome was incidence of TAI. RESULTS: There were 8562 patients, 37% were at high altitude and 63% at low altitude. High altitude patients were older (p < 0.01), more often Caucasian (p < 0.01) and had a higher ISS (p < 0.01). There was a significantly greater incidence of TAI at high altitude than low altitude (1.5% vs. 1.1%, p = 0.01). The median altitude was significantly higher for patients with a TAI than for patients without a TAI (5100 ft. vs. 1400 ft., p = 0.01). After adjustment, high altitude patients had 2-fold [OR: 2.4 (1.6, 3.7)] greater odds of having a TAI than low altitude patients. CONCLUSION: TAIs were more prevalent among high altitude injuries. Providers should be aware of the increased incidence of TAIs at high altitudes particularly when there is a delay in diagnosis and transfer to a trauma center with appropriate resources to manage these critical injuries. TAI screening at high altitude trauma centers may improve survival rates.

Feasibility and effects of galantamine on cognition in humans with cannabis use disorder.

BACKGROUND: As long-term use of medicinal and recreational cannabis becomes more common and concentrations of delta-9-tetrahydrocannabinol (THC) in cannabis increase, it is timely to identify strategies to counteract the cognitive effects of cannabinoids. OBJECTIVE: Galantamine is an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease and other dementias. This study aimed to investigate the feasibility of galantamine administration to individuals with cannabis use disorder (CUD), and the effects of galantamine on cognition. We hypothesized galantamine would be well tolerated and would not have procognitive effects in the absence of acute cannabis intoxication. METHODS: Thirty individuals with CUD (73.5% male, 26.5% female) participated in a randomized, double-blind, parallel-group trial. Participants completed a baseline session followed by a 10-day outpatient treatment period, during which they received either 8 mg/day of galantamine orally or placebo. Cognitive assessments were conducted at three time points and self-reported measures that may impact cognitive performance (cannabis withdrawal, craving, and mood) were completed at six time points. RESULTS: There were no significant differences in demographic and baseline variables between groups (galantamine vs. placebo). There were no significant adverse effects from galantamine. Cannabis withdrawal and craving continuously decreased over the study. We saw evidence of a modest improvement in cognitive outcomes during the 10-day period, exemplified by a statistically significant increase in measures of response inhibition (increased median reaction time on the Stop Signal Task), and a trend for improvement in measures of attention (increased RVP A'), for both groups. Analyses did not show, however, a significant main effect for treatment or treatment-by-time interactions. CONCLUSIONS: The findings of this pilot study support the feasibility of the administration of galantamine for individuals with CUD. Adequately powered, randomized, placebo-controlled trials are required to investigate the potential of galantamine to improve cognitive deficits associated with CUD.

Carvedilol does not reduce cocaine use in methadone-maintained cocaine users.

INTRODUCTION: The goal of this study was too test the efficacy of carvedilol (CAR), an adrenergic blocker, for reducing cocaine use in individuals with cocaine use disorder (CUD). We conducted a 17-week, double-blind, randomized controlled trial with 3 treatment arms: 25mg CAR, 50mg CAR, and placebo. METHODS: One hundred and six treatment-seeking opioid and cocaine-dependent participants, who were also maintained on methadone during study participation, were randomized to placebo (n=34), 25mg/day CAR (n=37) or 50mg/day CAR (n=35). The main outcome measures were cocaine and opioid use as assessed by urine drug screening and self-reported drug use. RESULTS: No significant group differences were found for treatment retention with 56% of the placebo, 76% of the 25mg and 66% of the 50mg CAR groups (p>0.05) completing treatment. The percentage (SD) of cocaine positive urines during the trial showed an overall treatment effect: 59.2 (38.9) for the placebo, 50.8 (33.8) for the 25mg and 75.1 (33.2) for the 50mg CAR group. In post hoc comparisons, neither the 25 nor 50mg CAR condition differed significantly from the placebo; however, the 25mg CAR group had a significantly lower proportion of cocaine-positive urines than the 50mg group. No significant group differences were found for the percentage of self-reported days of cocaine abstinence during the trial: 72.9 (25.3) for placebo, 72.9 (29) for CAR 25mg, and 59.3 (31.7) for CAR 50mg. Significant groups differences in the proportion of opioid positive urines submitted were not observed (p>0.05). Baseline cocaine withdrawal severity did not predict treatment response (p>0.05). CONCLUSIONS: These findings did not support the efficacy of CAR for the treatment of cocaine use in cocaine and opioid dependent participants maintained on methadone. Further, CAR doses >25mg should not be used to avoid possible increases in cocaine and opioid use.

A complex interplay between personality domains, marital status and a variant in CHRNA5 on the risks of cocaine, nicotine dependences and cocaine-induced paranoia.

BACKGROUND: Personality correlates highly with both cocaine and nicotine dependencies (CD, ND), and their co-morbid psychopathologies. However, little is known about the nature of these relationships. This study examined if environment (marriage) or genetics (a single SNP, CHRNA5*rs16969968) would moderate the correlation of personality with CD, ND and cocaine-induced paranoia (CIP) in African and European Americans (AAs, EAs). METHODS: 1432 EAs and 1513 AAs were examined using logistic regression. Personality was assessed by NEO-PI-R, while CD, ND and CIP were diagnosed according to DSM-IV. ND and CD were examined as binary traits and for the analysis of CIP, subjects were divided into 3 groups: (A) Controls with no CIP; (B) CD cases without CIP; and (C) CD cases with CIP. Multiple testing was Bonferroni-corrected. RESULTS: For CD and ND in the EA population, marital status proved to be a significant moderator in their relationship with openness only (OR = 1.90, 95%CI = 1.36-2.64, p = 1.54e-04 and OR = 2.12, 95%CI = 1.52-2.90, p = 4.65e-06 respectively). For CIP, marriage was observed to moderate its correlation with openness and neuroticism (OR = 1.39, 95%CI = 1.18-1.63, p = 7.64e-04 and OR = 1.26, 95%CI = 1.12-1.42, p = 1.27e-03 respectively). The correlations moderated by rs16969968 were those of conscientiousness and CD (OR = 1.62, 95%CI: 1.23-2.12, p = 8.94e-04) as well as CIP (OR = 1.21, 95%CI: 1.11-1.32, p = 4.93e-04 when comparing group A versus group C). No significant interactions were observed in AA population. The Bonferroni-corrected significance threshold was set to be 1.67e-03. CONCLUSION: The role of personality in CD and CIP may be interceded by both environment and genetics, while in ND by environment only.

Sertraline delays relapse in recently abstinent cocaine-dependent patients with depressive symptoms.

AIMS: Whether the selective serotonin re-uptake inhibitor sertraline at 200 mg/day delays relapse in recently abstinent cocaine-dependent individuals. DESIGN: The study involved a 12-week, double-blind, placebo-controlled clinical trial with 2-week residential stay followed by 10-week out-patient participation. SETTING: Veterans Affairs residential unit and out-patient treatment research program. PARTICIPANTS: Cocaine-dependent volunteers (n = 86) with depressive symptoms (Hamilton score > 15), but otherwise no major psychiatric or medical disorder or contraindication to sertraline. MEASUREMENTS: Participants were housed on a drug-free residential unit (weeks 1-2) and randomized to receive sertraline or placebo. Participants then participated on an out-patient basis during weeks 3-12 while continuing to receive study medication. Patients participated in a day substance abuse/day treatment program during weeks 1-3 and underwent weekly cognitive behavioral therapy during weeks 4-12. The primary outcome measure was thrice-weekly urine results and the secondary measure was Hamilton Depression scores. FINDINGS: Pre-hoc analyses were performed on those who participated beyond week 2. Generally, no group differences in retention or baseline characteristics occurred. Sertraline patients showed a trend towards longer time before their first cocaine-positive urine ('lapse', χ(2) = 3.67, P = 0.056), went significantly longer before having two consecutive urine samples positive for cocaine ('relapse', χ(2) = 4.03, P = 0.04) and showed significantly more days to lapse (26.1 ± 16.7 versus 13.2 ± 10.5; Z = 2.89, P = 0.004) and relapse (21.3 ± 10.8 versus 32.3 ± 14.9; Z = 2.25, P = 0.02). Depression scores decreased over time (F = 43.43, P < 0.0001), but did not differ between groups (F = 0.09, P = 0.77). CONCLUSIONS: Sertraline delays time to relapse relative to placebo in cocaine-dependent patients who initially achieve at least 2 weeks of abstinence.

5-HTTLPR as a potential moderator of the effects of adverse childhood experiences on risk of antisocial personality disorder.

INTRODUCTION: Antisocial personality disorder (ASPD) frequently co-occurs with substance dependence (SD). A functional polymorphism (5-HTTLPR) in the serotonin transporter gene has been widely studied as a risk factor for a variety of psychopathologic conditions including aggressive/violent behavior. Childhood abuse is an important predictor of ASPD. We examined 5-HTTLPR genotype and adverse childhood events (ACEs) as risk factors for ASPD in a SD sample. MATERIALS AND METHODS: Study participants [602 European-Americans (EAs) and 779 African-Americans (AAs)] were interviewed to obtain lifetime diagnoses of ASPD and SD and information on ACEs. Triallelic genotypes for 5-HTTLPR were obtained using standard methods. We used logistic generalized estimating equations regression to examine ACEs and 5-HTTLPR genotype and their interaction as predictors of ASPD, separately by population group. RESULTS: There were 203 (14.7%) participants diagnosed with ASPD. The frequency of the low-activity 5-HTTLPR S' allele did not differ by ASPD diagnosis, and there was no overall 5-HTTLPR×ACE interaction. However, among European-Americans, male sex (odds ratio=3.36; P<0.001) and ACE history (odds ratio=1.47; P=0.002) were significant predictors of ASPD. Among AAs, there was a significant interaction of sex×5-HTTLPR genotype×ACEs (χ=13.92, P<0.001). Among AA men, each additional ACE significantly increased the odds of ASPD irrespective of genotype, whereas among AA women, the effect of ACEs on ASPD was significant only among S' homozygotes. However, these results are limited by the small sample size in each subgroup, (particularly AA women with S'S' genotype; N=7) and require replication. CONCLUSIONS: Childhood maltreatment contributes to the risk of ASPD, an effect for which there is preliminary evidence of moderation by 5-HTTLPR genotype in AA women.

Galantamine improves sustained attention in chronic cocaine users.

Chronic cocaine users are known to have cognitive deficits that are predictive of poor treatment response. Whether these deficits improve with medications targeting specific cognitive functions has not been examined in previous studies. The goal of this study was to evaluate galantamine's efficacy on selected cognitive outcomes, including measures of sustained attention, response inhibition, and attentional bias in recently abstinent cocaine users. Galantamine, a reversible and competitive inhibitor of acetylcholinesterase, is used clinically in the treatment of Alzheimer's dementia. In a randomized, double-blind, parallel-group study, 34 participants were randomized to galantamine (8 mg/day) or placebo treatment for 10 days. Cognitive and self-report mood measures were obtained at baseline and on Days 5 and 10 after the initiation of treatment. Galantamine treatment, compared to placebo, improved the reaction time, F(2, 50) = 8.6, p < .01, detection sensitivity (A'), F(2, 50) = 4.9, p < .03, number of hits, F(2, 50) = 4.2, p < .04, and number of correct rejections, F(2, 50) = 5.6, p < .02, on the Rapid Visual Information Processing task. With the exception of speeding the reaction time on the Stroop, galantamine did not affect performance on other tasks, (p > .05). These results demonstrate that medications can enhance cognitive function (e.g., sustained attention) in abstinent cocaine users. The potential efficacy of galantamine as a treatment for cocaine abuse needs to be further evaluated in clinical trials.

Randomized, double blind, placebo-controlled trial of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients.

UNLABELLED: This study examined the dose-related efficacy of disulfiram for treating cocaine dependence in methadone-stabilized cocaine dependent participants. DESIGN: One hundred and sixty-one cocaine- and opioid-dependent volunteers were entered into a 14-week, double blind, randomized, placebo-controlled clinical trial at two sites. METHODS: Participants were stabilized on methadone during weeks 1-2 and received disulfiram at 0, 62.5, 125 or 250 mg/day during weeks 3-14. All participants also received weekly cognitive behavioral therapy. Thrice-weekly urine samples and weekly self-reported drug use assessments were obtained. RESULTS: Baseline subject characteristics, retention and drug use did not differ across groups. Outcome analyses were performed on those who participated beyond week 2. Opioid-positive urine samples and self-reported opioid use did not differ by treatment group. The prevalence of alcohol use was low prior to and during the trial and did not differ by treatment group. Cocaine-positive urines increased over time in the 62.5 and 125 mg disulfiram groups and decreased over time in the 250 mg disulfiram and placebo groups (p < 0.0001). Self-reported cocaine use increased in the 125 mg disulfiram group relative to the other three treatment groups (p = 0.04). CONCLUSIONS: Disulfiram may be contraindicated for cocaine dependence at doses <250 mg/day. Whether disulfiram at higher doses is efficacious in reducing cocaine use in dually cocaine and opioid dependent individuals needs to be determined.

The safety of modafinil in combination with oral ∆9-tetrahydrocannabinol in humans.

Marijuana (cannabis) is the most widely used illicit substance globally, and cannabis use is associated with a range of adverse consequences. Currently, no medications have been proven to be effective for the treatment of cannabis addiction. The goals of this study were to examine the safety and efficacy of a potential treatment medication, modafinil, in combination with oral ∆9-tetrahydrocannabinol (THC). Twelve male and female occasional cannabis users participated in an outpatient double-blind, placebo-controlled, crossover study. Across four sessions, participants were randomly assigned to a sequence of four oral treatments: (1) 400 mg modafinil+placebo, (2) 15 mg THC+placebo, (3) 400 mg modafinil+15 mg THC, or (4) placebo+placebo. Outcome measures included heart rate, blood pressure, performance on the Rapid Visual Information Processing (RVIP), and the Hopkins Verbal Learning Test (HVLT), and subjective measures. Oral THC increased heart rate, and produced increased subjective ratings of feeling "high" and "sedated," as well as increased ratings of euphoria. Modafinil alone increased the Profiles of Mood States (POMS) subscales of vigor and tension. These findings support the safety of modafinil in combination with THC. The effects of modafinil in combination with a range of doses of THC need to be determined in future studies.

The safety and efficacy of varenicline in cocaine using smokers maintained on methadone: a pilot study.

In this double-blind, placebo-controlled trial, we compared varenicline (2 mg) to placebo for treatment for cocaine and tobacco dependence in 31 methadone-maintained subjects. Subjects received weekly counseling during the 12-week study participation. Our results indicate that varenicline is safe to give to this subject population, as there were no adverse events related to medication during this study. Varenicline was no more effective than placebo for abstinence from cocaine. Treatment with varenicline was associated with a reduced number of cigarettes smoked per day, even though subjects received only a brief education for smoking cessation. The self-report reduction in smoking was corroborated by CO levels and the Fagerström Test of Nicotine Dependence. However, self-ratings of positive mood on the Positive Affect Negative Affect Schedule did significantly decrease in the varenicline group as compared to the placebo group, although this appears to be due to randomization differences related to lifetime depression diagnosis. These preliminary findings may point to potential therapeutic value of varenicline for smoking cessation in cocaine users maintained on methadone.

Variation in the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 and its interaction with recent tobacco use influence cognitive flexibility.

Variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster have been associated with nicotine dependence (ND) and ND-related traits. To evaluate a potential underlying mechanism for this association, we investigated the effects of 10 variants in this gene cluster and their interactive effects as a result of recent smoking on cognitive flexibility, a possible mediator of genetic effects in smokers. Cognitive flexibility of 466 European Americans (EAs; 360 current smokers) and 805 African Americans (AAs; 635 current smokers) was assessed using the Wisconsin Card Sorting Test. The main effects of variants and haplotypes and their interaction with recent smoking on cognitive flexibility were examined using multivariate analysis of variance and the haplotype analysis program HAPSTAT. In EAs, the major alleles of five variants (CHRNA5-rs3841324-22 bp-insertion-allele, CHRNA5-rs615470-C-allele, CHRNA3-rs6495307-C-allele, CHRNA3-rs2869546-T-allele, and CHRNB4-rs11637890-C-allele) were associated with significantly greater perseverative responses (P=0.003-0.017) and perseverative errors (P=0.004-0.026; recessive effect). Among EAs homozygous for the major alleles of each of these five variants, current smokers made fewer perseverative responses and perseverative errors than did past smokers. Significant interactive effects of four variants (rs3841324, rs615470, rs6495307, and rs2869546) and current smoking on cognitive flexibility were observed (perseverative responses (P=0.010-0.044); perseverative errors (P=0.017-0.050)). However, in AAs, 10 variants in this gene cluster showed no apparent effects on cognitive flexibility. These findings suggest that variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster influences cognitive flexibility differentially in AAs and EAs and that current smoking moderates this effect. These findings could account in part for differences in ND risk associated with these variants in AAs and EAs.

Behavioral effects of gamma-hydroxybutyrate in humans.

Despite the therapeutic use and abuse potential of gamma-hydroxybutyrate (GHB or Xyrem), relatively few studies have examined the behavioral effects of GHB in humans under controlled laboratory conditions. Thus, this eight-session study examined in 10 non-substance-abusing volunteers the behavioral effects of GHB at each of the following doses: 0, 0.32, 0.56, 0.75, 1.0, 1.8, 2.4, 3.2 g/70 kg, orally. Order of dose testing was random, except that the first two participants received active doses in ascending order and 2.4 g/70 kg was always tested before 3.2 g/70 kg. Before drug administration and at several postdrug time points, self-report, observer report, physiological, and psychomotor performance measures were obtained. Analyses based on area under the curve showed that GHB produced dose-related increases in subjective ratings of sedative-like, stimulant-like, positive mood, and dissociative effects, but no changes in psychomotor performance measures or blood pressure. Analyses based on peak effects generally showed dose-related increases in ratings indicating sedative-like, dissociative, and drug liking, although some measures showed U-shaped dose-related changes. These initial findings suggest that GHB at doses of 0.32-3.2 g/70 kg produces dissociative, sedating and some stimulant-like effects in humans without a history of sedative abuse.

Variation in nicotinic acetylcholine receptor genes is associated with multiple substance dependence phenotypes.

There is shared genetic risk for dependence on multiple substances, and the nicotinic receptor gene cluster on chromosome 15 harbors multiple polymorphisms that associate to this risk. Here, we report the results of an association study with 21 SNPs genotyped across the CHRNA5, CHRNA3, and CHRNB4 loci on chromosome 15q25.1. The sample consists of a discovery set (N=1858) of European-American and African-American (AA) families, ascertained on the basis of a sibling pair with cocaine and/or opioid dependence, and a case-control replication sample (N=3388) collected for association studies of alcohol, cocaine, and opioid dependence. We tested the SNPs for association with lifetime cocaine, opioid, nicotine, and alcohol dependence. We replicated several previous findings, including associations between rs16969968 and nicotine dependence (P=0.002) and cocaine dependence (P=0.02), with opposite risk alleles for each substance. We observed these associations in AAs, which is a novel finding. The strongest association signal in either sample was between rs684513 in CHRNA5 and cocaine dependence (OR=1.43, P=0.0004) in the AA replication set. We also observed two SNPs associated with alcohol dependence, that is, rs615470 in CHRNA5 (OR=0.77, P=0.0006) and rs578776 (OR=0.78, P=0.001). The associations between CD and rs684513, AD and rs615470, and AD and rs578776 remained significant after a permutation-based correction for multiple testing. These data reinforce the importance of variation in the chromosome 15 nicotinic receptor subunit gene cluster for risk of dependence on multiple substances, although the direction of the effects may vary across substances.

Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder.

FKBP5 regulates the cortisol-binding affinity and nuclear translocation of the glucocorticoid receptor. Polymorphisms at the FKBP5 locus have been associated with increased recurrence risk of depressive episodes and rapid response to antidepressant treatment. A recent study showed that FKBP5 genotypes moderated the risk of post-traumatic stress disorder (PTSD) symptoms associated with childhood maltreatment. One thousand one hundred forty-three European Americans (EAs) and 1284 African Americans (AAs) recruited for studies of the genetics of substance dependence were also screened for lifetime PTSD. Four single-nucleotide polymorphisms (SNPs) in FKBP5, rs3800373, rs9296158, rs1360780, and rs9470080, were genotyped on the complete sample. Logistic regression analyses were performed to explore the interactive effect of FKBP5 polymorphisms and childhood adversity on the risk for PTSD. After correction for multiple testing, childhood adversity significantly increased the risk for PTSD. FKBP5 genotypes were not associated with the development of the disorder. In AAs, one of the SNPs, rs9470080, moderated the risk of PTSD that was associated with childhood abuse. Without childhood adverse experiences, participants with the TT genotype of this SNP had the lowest risk for PTSD, whereas they had the highest risk for PTSD after childhood adversity exposure. In addition, in EAs, alcohol dependence was observed to interact with childhood adverse experiences, and also FKBP5 polymorphisms, to increase the risk for PTSD. This study provides further evidence of a gene x environment effect of FKBP5 and childhood abuse on the risk for PTSD in AAs. Further study is required in other populations.

Confirmation and generalization of an alcohol-dependence locus on chromosome 10q.

Several genome scans on alcohol dependence (AD) and AD-related traits have been published. In this article, we present the results of a genome-wide linkage scan on AD and several related traits in 322 European-American (EA) families, and results of additional analysis in 335 African-American (AA) families that were the subject of a previous report. All families were initially ascertained for cocaine and/or opioid dependence. Non-parametric linkage analysis in the EA sample revealed suggestive linkages on chromosomes 7 (LOD=2.1 at 82.8 cM, p=0.0009) and 10 (LOD=3.0 at 137.7 cM, p=0.0001). The chromosome 10 linkage peak is 20 cM distal from a genome-wide significant linkage peak we observed previously in the AA sample. Parametric linkage analysis on chromosome 10 (assuming a recessive model, 80% penetrance, disease allele frequency=0.3) resulted in LOD scores of 2.7 at 136.7 cM and 1.9 at 121.7 cM in the EA and AA samples, respectively, with a combined sample genome-wide significant LOD score of 4.1 at 131.7 cM. To reduce heterogeneity of the AD phenotype, we also assessed linkage of chromosome 10 markers with the presence of alcohol withdrawal symptoms, one of the seven components of the DSM-IV diagnosis of AD. Suggestive evidence for linkage was observed in both populations with only 5 cM separating the location of the peak LOD scores despite a loss of power due to a smaller number of families informative for this trait. Results of our study confirm a chromosome 10 risk locus for AD in two genetically distinct populations and suggest that this locus may correspond more precisely to a specific component of the disorder.

Effect of PTSD diagnosis and contingency management procedures on cocaine use in dually cocaine- and opioid-dependent individuals maintained on LAAM: a retrospective analysis.

This randomized clinical trial retrospectively examined the effect of post-traumatic stress disorder (PTSD) and contingency management (CM) on cocaine use in opioid and cocaine dependent individuals maintained on high or low-dose LAAM randomly assigned to CM or a yoked-control condition. Cocaine-positive urines decreased more rapidly over time in those without PTSD versus those with PTSD in the noncontingency condition. In participants with PTSD, CM resulted in fewer cocaine-positive urines compared to the noncontingent condition. This suggests that CM may help improve the potentially worse outcomes in opioid- and cocaine-dependent individuals with PTSD compared to those without PTSD. (Am J Addict 2010;00:1-9).

Adverse childhood events as risk factors for substance dependence: partial mediation by mood and anxiety disorders.

AIMS: Adverse childhood events (ACEs) are associated with negative health outcomes. We examined ACEs as risk factors for substance dependence (SD) and the mediating effects of mood and anxiety disorders on the relations between ACEs and SD risk. DESIGN: We compared early life experiences in 2061 individuals with a lifetime diagnosis of alcohol, cocaine, or opioid dependence and 449 controls. MEASUREMENTS: Diagnostic and ACE data were obtained using the Semi-Structured Assessment for Drug Dependence and Alcoholism. FINDINGS: Childhood abuse or exposure to violent crime was positively related to the number of lifetime mood and anxiety disorders and to SD risk. Mood and anxiety disorders had their first onset a mean of nearly 3 years before the first SD diagnosis and partially mediated the effect of ACEs on SD risk. CONCLUSION: ACEs appear to contribute additively to the risk of SD, with mood and anxiety disorders in the causal path for a portion of this risk. The identification and effective treatment of mood and anxiety disorders associated with ACEs could reduce the risk of developing SD.

ADH1A variation predisposes to personality traits and substance dependence.

Human personality traits are strong predictors or characteristics of many psychiatric disorders including substance dependence (SD). Recently, significant associations between alcohol dehydrogenase type 1A gene (ADH1A) and SD have been reported, which led us to investigate the impact of ADH1A variation on personality traits and risk of SD. Five hundred fifty-eight subjects with SD [398 European-Americans (EAs) and 160 African-Americans (AAs)], 517 college students (384 EAs and 133 European-origin Hispanics), and 448 healthy subjects (385 EAs, 48 AAs, and 15 European-origin Hispanics) participated. Personality traits were assessed in 247 subjects with SD (179 EAs and 68 AAs), all 517 college students, and 332 healthy subjects (285 EAs, 40 AAs, and 7 European-origin Hispanics). The relationships between ADH1A and personality traits were comprehensively examined using stepwise multivariate analysis of covariance (MANCOVA), and then decomposed by stepwise analysis of covariance (ANCOVA). The relationship between ADH1A and SD was examined using stepwise logistic regression analysis. Admixture effects on analyses were considered. Overall, Agreeableness and Conscientiousness were associated with the diplotypes, haplotypes, genotypes, and/or alleles of ADH1A in three of four phenotype groups including EA SD subjects, healthy subjects, and AA SD subjects (1.7 x 10(-4)

Atomoxetine attenuates dextroamphetamine effects in humans.

BACKGROUND: Although preclinical studies support the contribution of the noradrenergic system activation in mediating the acute effects of amphetamines, these findings have not been followed up in clinical studies. OBJECTIVES: To examine the effects of atomoxetine, a norepinephrine transporter inhibitor, on subjective, physiological, and plasma cortisol responses to dextroamphetamine in 10 healthy volunteers. METHODS: Subjects were randomly assigned to a sequence of atomoxetine (40 mg/day) or placebo treatments each lasting for 4 days. On Day 4 of each treatment period, responses to a single 20 mg/70 kg dose of dextroamphetamine were assessed. RESULTS: Atomoxetine treatment attenuated dextroamphetamine-induced increases in systolic and diastolic blood pressure and plasma cortisol as well as the self-report ratings of "stimulated," "high," and "good drug effects." CONCLUSIONS: These findings are consistent with previous preclinical studies supporting the role of the noradrenergic system in mediating acute amphetamine responses. SCIENTIFIC SIGNIFICANCE: Atomoxetine's capacity to attenuate some of the physiological and subjective responses to dextroamphetamine supports its potential use for stimulant addiction.