Sarra L. Hedden

The Role of Cystine-Glutamate Exchange in Nicotine Dependence in Rats and Humans

BACKGROUND The present study determined if, akin to cocaine, nicotine self-administration in rats induces adaptations in the expression of glutamate transporters and cystine-glutamate exchangers in brain nuclei implicated in reinforcement and if treating cigarette smokers with a drug that restores cystine-glutamate exchange affects the number of cigarettes smoked. METHODS Rats self-administered nicotine intravenously for 12 hours/day or received nicotine through osmotic minipumps for 21 days. Somatic signs of withdrawal were measured and immunoblotting was performed 12 hours after the last nicotine exposure to determine if the catalytic subunit of the cystine-glutamate exchanger, xCT, or the glial glutamate transporter, GLT-1, were altered in the ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex, or amygdala. For the smoking reduction study in humans, nicotine-dependent smokers were treated for 4 weeks with N-acetylcysteine (2400 mg daily) to promote cystine-glutamate exchange or placebo. Participants provided weekly ratings of withdrawal symptoms, craving, and carbon monoxide (CO) measurements and logged daily cigarette and alcohol use. RESULTS Rats receiving nicotine via self-administration or minipumps displayed somatic signs of withdrawal, but only nicotine self-administering rats showed decreased xCT expression in the nucleus accumbens and VTA and decreased GLT-1 expression in the nucleus accumbens. Human smokers treated with N-acetylcysteine reported a reduction in cigarettes smoked, and there was no effect of N-acetylcysteine on estimates of CO levels, craving, or withdrawal. CONCLUSIONS These results indicate that the cystine-glutamate exchanger and the glial glutamate transporter are downregulated after nicotine self-administration, and augmenting exchanger activity with N-acetylcysteine reduced the number of cigarettes smoked in nicotine-dependent individuals.

Modafinil and Cocaine Interactions

This Phase I trial evaluated the interaction between modafinil steady-state and cocaine. Twelve non-treatment seeking, cocaine dependent volunteers received four sets of randomized blinded infusions of saline, 20 mg IV cocaine, and 40 mg IV cocaine. Modafinil was given open label at 0 mg, 400 mg, or 800 mg. Modafinil combined with IV cocaine did not result in any significant hemodynamic interactions. Modafinil significantly dampened scores on Visual Analog Scale measures as compared to baseline cocaine conditions. No significant alterations in labs occurred. Further outpatient trials of modafinil appear to be warranted.

Patterns of illegal drug use among an adult alcohol dependent population: Results from the National Survey on Drug Use and Health

The use of illegal drugs is common in alcohol dependence and significant psychological and social consequences are associated with the concurrent use of alcohol and illegal drugs. However, little literature has examined the patterns of concurrent-drug use in alcohol dependent individuals. A latent class analysis (LCA) was used to determine whether patterns of past year illegal drug use existed in a national sample of 6059 alcohol dependent respondents of the combined 2005, 2006 and 2007 National Survey on Drug Use and Health. Multinomial logistic regression was then used to determine whether demographic variables, mental health disturbance and social consequences were predictive of drug use classes. Results of the LCA demonstrated a 5-class solution with optimal fit deduced by Bayesian Information Criterion minima. The five classes included: a close to zero probability of illegal drug use (class 1: 65%), medium marijuana, medium sedatives/tranquilizers and high analgesics (class 2: 7%), high marijuana, medium cocaine use (class 3: 21%), high probabilities of marijuana, cocaine, sedatives and analgesic use (class 4: 6%) and a high concurrent-drug use except other hallucinogens (class 5: 1%). Regression results suggest that younger age, comorbidity, engaging in deviant behaviors, sexually transmitted infection and incarceration are associated with concurrent illegal drug use in alcohol dependent individuals. Findings advocate that more intense psychiatric and drug dependence treatment resources may be needed for concurrent-drug using alcohol dependent populations and provide evidence for targeted prevention and treatment interventions.

Adolescent drug dealing and race/ethnicity: A population-based study of the differential impact of substance use on involvement in drug trade

Background: Among adolescents, peers are an important source of drug procurement. However, little is known about factors associated with youths’ involvement in drug trade. Objectives: The aim of the study is to identify substance use behaviors and contextual factors related to drug dealing among Black and White adolescents. Methods: The sample consisted of 13,706 White and Black youths who completed the National Survey on Drug Use and Health. Separate backward logistic regression was used to identify substance use behaviors and contextual factors associated with drug dealing among Black and White youths. Results: Among White youths, drug dealing was associated with use of marijuana, hallucinogens, cocaine, prescription drug misuse, availability of cocaine, and socioeconomic status (SES). Among Black youths, marijuana use and availability of crack and marijuana were associated with drug dealing. Conclusions and Scientific Significance: For White youths, substance use seems to be more relevant to drug dealing. Consequently, preventing and treating substance abuse may reduce involvement in the illegal distribution of drugs among White youths. More research is needed to identify risk and protective factors for drug dealing among Black adolescents.

Randomization in substance abuse clinical trials

BackgroundA well designed randomized clinical trial rates as the highest level of evidence for a particular interventions efficacy. Randomization, a fundamental feature of clinical trials design, is a process invoking the use of probability to assign treatment interventions to patients. In general, randomization techniques pursue the goal of providing objectivity to the assignment of treatments, while at the same time balancing for treatment assignment totals and covariate distributions. Numerous randomization techniques, each with varying properties of randomness and balance, are suggested in the statistical literature. This paper reviews common randomization techniques often used in substance abuse research and an application from a National Institute on Drug Abuse (NIDA)-funded clinical trial in substance abuse is used to illustrate several choices an investigator faces when designing a clinical trial.ResultsComparisons and contrasts of randomization schemes are provided with respect to deterministic and balancing properties. Specifically, Monte Carlo simulation is used to explore the balancing nature of randomization techniques for moderately sized clinical trials. Results demonstrate large treatment imbalance for complete randomization with less imbalance for the urn or adaptive scheme. The urn and adaptive randomization methods display smaller treatment imbalance as demonstrated by the low variability of treatment allocation imbalance. For all randomization schemes, covariate imbalance between treatment arms was small with little variation between adaptive schemes, stratified schemes and unstratified schemes given that sample sizes were moderate to large.ConclusionWe develop this paper with the goal of reminding substance abuse researchers of the broad array of randomization options available for clinical trial designs. There may be too quick a tendency for substance abuse researchers to implement the fashionable urn randomization schemes and other highly adaptive designs. In many instances, simple or blocked randomization with stratification on a major covariate or two will accomplish the same objectives as an urn or adaptive design, and it can do so with more simply implemented schedules and without the dangers of overmatching. Furthermore, the proper analysis, fully accounting for the stratified design, can be conducted.

Differences between adult non-drug users versus alcohol, cocaine and concurrent alcohol and cocaine problem users.

Concurrent drug use is a serious public health concern with significant morbidity and mortality associated with the combined use of alcohol and cocaine. Multinomial logistic regression was used to assess differences between non-drug users and alcohol, cocaine and concurrent problem users incorporating data from the 2005 National Survey on Drug Use and Health. Results demonstrated that alcohol and cocaine use is associated with mental health disturbance, other drug use and adverse social consequences. Furthermore, concurrent users were more likely to report cigarette and marijuana use as well as lifetime STDs and arrest for breaking the law. Study results have implications for planning prevention and treatment services differentially for alcohol, cocaine and concurrent users and support the need for more intense resources allocated to the prevention and treatment of the concurrent use of alcohol and cocaine.

The association between executive functioning and motivation to enter treatment among regular users of heroin and/or cocaine in Baltimore, MD

This study explored the association between readiness to enter treatment and performance on the Wisconsin Card Sorting Test (WCST), a measure of problem solving ability and executive functioning. Data for this analysis was collected on 258 current regular users of heroin and/or cocaine as part of an epidemiologic study on executive function and drug use. A structural equation model was used to test the hypotheses that poorer performance on the WCST would predict lower scores on two latent constructs measuring motivation to change drug use. Specifically, poorer performance on the WCST was associated with lower recognition of problem use. Associations between treatment enrollment within the past six months and regular use of more than one drug were also observed. Findings highlight the importance of considering cognitive impairment in programs targeting active drug users and promoting treatment participation.

Patterns of Cognitive Impairments Among Heroin and Cocaine Users The Association With Self-Reported Learning Disabilities and Infectious Disease

This study used data from six neuropsychological measures of executive function (EF) and general intellectual functioning (GIF) administered to 303 regular users of heroin and/or cocaine as indicators in a latent profile analysis (LPA). Results indicated the presence of three profiles: impaired GIF and EF profile (30.8%), intact GIF and EF profile (58.8%), and high GIF/intact EF profile (10.4%). Using a multinomial logistic regression, it was determined that individuals who reported being diagnosed with either a learning disability (LD) and/or attention-deficit/hyperactivity disorder (ADHD) were more likely to be in the impaired GIF and EF profile than other profiles. Results from a logistic regression indicated that the impaired GIF and EF profile was associated with a greater prevalence of past hepatitis B and/or C infection. Implication for harm reduction and treatment programs and the need to take into account individuals with LD and ADHD are discussed.

Alcohol, drug, and sexual risk behavior correlates of recent transactional sex among female black South African drug users

Introduction: Transactional sex among black South African women has become a mode of economic survival putting them at higher risk for HIV and other infectious disease. Methods: In order to inform HIV interventions, drug, and sexual risk behavior correlates of recent transactional sex among a descriptive epidemiological, cross-sectional sample of 189, black South African women in Pretoria were examined using log binomial regression. Results: Prevalence of HIV seropositivity was extremely high among non-transactional sex workers (47.1%) and transactional sex workers (54.6%), albeit not significantly different. Adjusted regression results indicated that the probability of transactional sex was greater for drug using women who tested positive for cocaine use [adjusted prevalence ratio (APR) = 1.3, 95% CI = 1.1, 1.5] and knew of anyone who died of AIDS (APR = 1.5, 95% CI = 1.1, 2.1). The probability of transactional sex was lower for female drug users who reported greater education (APR = 0.6, 95% CI = 0.4, 0.8), condom use in their first sexual encounter (APR = 0.7, 95% CI = 0.6, 1.0), or reported a recent steady sexual partnership (APR = 0.8, 95% CI = 0.7, 0.9). Conclusions: Drug use-related interventions for female transactional sex workers may need to focus on methods for the reduction of not only drug use, especially cocaine use, but also the reduction of sexual risk behaviors.

The Association Between Poly-Substance Use, Coping, and Sex Trade Among Black South African Substance Users

The current study examined the relationship between poly-substance use and sex trade among 343 black South African substance users recruited from the Pretoria region between 2002 and (57% males; mean age 24 years). The assessment comprised a HIV-risk behavior interview, urinalysis to confirm self-report of drug use, and an HIV test. Logistic regression analyses indicated poly-substance use was positively associated with sex trade among persons using drugs to cope with stress. Results indicate the importance of considering coping strategies as modifiable psychosocial factor related to sexual risk-taking behaviors and substance use. The studys implications and limitations are discussed.