Nathasha R. Moallem

Sex differences in striatal dopamine D2/D3 receptor availability in smokers and non-smokers.

In previous research, nicotine-dependent men exhibited lower putamen D2/D3 dopamine-receptor availability than non-smokers (Fehr et al. 2008), but parallel assessments were not performed in women. Women and men (19 light smokers, 18 non-smokers) were tested for differences due to sex and smoking in striatal D(2)/D(3) dopamine-receptor availability, using positron emission tomography with [(18)F]fallypride. Receptor availability was determined using a reference region method, in striatal volumes and in whole-brain, voxel-wise analysis. Significant sex × smoking interactions were observed in the caudate nuclei and putamen. Post-hoc t tests showed that male smokers had significantly lower D(2)/D(3) dopamine-receptor availability than female smokers (-17% caudate, -21% putamen) and male non-smokers (-15% caudate, -16% putamen). Female smokers did not differ from non-smokers. Whole-brain analysis demonstrated no statistically significant voxels or clusters. These results suggest that low receptor availability may confer vulnerability to nicotine dependence or that smoking selectively affects D2/D3 receptor down-regulation in men but not women.

The Effects of Naltrexone on Subjective Response to Methamphetamine in a Clinical Sample: a Double-Blind, Placebo-Controlled Laboratory Study

Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of ‘crave drug,’ ‘stimulated,’ and ‘would like drug access,’ decreased the the post-MA administration timecourse of ‘anxious’ and increased ratings of ‘bad drug effects,’ as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA.

The effects of varenicline on stress-induced and cue-induced craving for cigarettes

BACKGROUND Varenicline is a partial agonist of the α4β2 nicotinic acetylcholine receptor approved by the FDA for the treatment of nicotine dependence. While the clinical efficacy of varenicline for smoking cessation is well-supported, its biobehavioral mechanisms of action remain poorly understood. This randomized, crossover, placebo-controlled, human laboratory study combines guided imagery stress exposure with in vivo presentation of cigarette cues to test the effects of varenicline on stress-induced and cue-induced craving for cigarettes. METHOD A total of 40 (13 females) daily smokers (≥10 cigarettes per day) completed a guided imagery exposure (stress and neutral) followed by the presentation of cigarette cues at the target dose of varenicline (1mg twice per day) and on matched placebo. RESULTS Multilevel regression models revealed a significant main effect of varenicline (p<.01) such that it reduced cigarette craving across the experimental paradigm, compared to placebo. There was also a significant medication×stress×trial interaction indicating that varenicline attenuated cue induced craving following neutral imagery but not when cues were preceded by stress induction (i.e., stress+cues). CONCLUSIONS These results elucidate the biobehavioral effects of varenicline for nicotine dependence and suggest that varenicline-induced amelioration of cigarette craving is unique to tonic craving and cue-induced craving following neutral imagery but does not extend to the combination of stress plus cues.

DIMENSIONS OF IMPULSIVITY AMONG HEAVY DRINKERS, SMOKERS, AND HEAVY DRINKING SMOKERS: SINGULAR AND COMBINED EFFECTS

Alcohol use and cigarette smoking commonly co-occur. The role impulsivity may play as a common underlying mechanism in alcohol use and cigarette smoking is of particular interest due to emerging evidence of it being a critical component across multiple forms of addiction. Impulsivity can be examined through several constructs including, risky decision-making, response inhibition, and delay reward discounting. Impulsivity and each of these specific constructs play significant roles in the initiation of drug use, continued use despite negative consequences, and potential to relapse. This study used three behavioral tasks to measure risky decision-making (balloon analog risk test; BART), response inhibition (stop signal task; SST), and delay reward discounting (delay discounting task; DDT). This study advances research on impulsivity and substance use by parsing out the various components of impulsivity and examining them across three groups, heavy drinkers only (HD) (N=107), smokers only (S) (N=67), and heavy drinking smokers (HDS) (N=213). Participants completed questionnaires, interviews, and neurocognitive tasks including the SST, BART, and DDT. Analyses supported an additive effect of alcohol and nicotine use in delay reward discounting. Heavy drinking smokers displayed steeper delay discounting of small rewards than did smokers only (p<.05) and heavy drinkers only (p<.05). This additive effect of smoking and drinking was not observed for risky decision-making and response inhibition, suggesting specificity of the effects for delay reward discounting. These findings indicate that those who both drink heavily and smoke cigarettes daily have increased delay reward discounting, than those in the S and HD groups. Future studies should examine these constructs longitudinally, as well as incorporate genetic and/or a neuroimaging component to these group comparisons in order to ascertain the biological bases of these behavioral findings.

QUETIAPINE IMPROVES RESPONSE INHIBITION IN ALCOHOL DEPENDENT PATIENTS: A PLACEBO-CONTROLLED PILOT STUDY

RATIONALE Quetiapine has been shown to be a promising medication for the treatment of alcoholism. As an atypical antipsychotic medication with antagonist activity at D1 and D2, 5-HT(1A) and 5-HT(2A), H(1) and α1 and α2 receptors, quetiapine has been found to decrease impulsivity in other psychiatric disorders but its effects on impulsivity have not been studied in alcohol dependent patients. OBJECTIVE This study seeks to test the effects of quetiapine on a specific dimension of impulsivity, namely response inhibition. This pilot study seeks to further elucidate the mechanisms of action of quetiapine for alcohol use disorders. METHOD A total of 20 non-treatment seeking alcohol dependent individuals were randomized to one of the following conditions in a double-blind, placebo-controlled design: (1) quetiapine (400 mg/day); or (2) matched placebo. Participants completed two counterbalanced intravenous placebo-alcohol administration sessions as well as behavioral measure of response inhibition (i.e. stop signal task) pre and post placebo-alcohol administration sessions. RESULTS Analyses revealed a significant effect of quetiapine in improving response inhibition as measured by the stop signal task. These results provide preliminary evidence suggesting that quetiapine improves response inhibition in alcohol dependent patients, as compared to placebo. CONCLUSION This pilot study contributes a novel putative mechanism of action of quetiapine in alcoholism, namely an improvement in response inhibition.

The relationship between methamphetamine and alcohol use in a community sample of methamphetamine users

BACKGROUND While methamphetamine (MA) and alcohol are often used in combination, little is known about the pattern of co-use between these substances. The goal of the present study is to examine the relationship between MA use and alcohol use in a community sample of non-treatment seeking regular MA users. METHODS Participants completed a face-to-face assessment battery, which included a diagnostic interview for MA dependence and the timeline follow-back interview for both alcohol and MA use over the past 30 days. Sixty regular MA and alcohol users supplied data for 1800 person-days. RESULTS Compared with non-drinking days, drinking days and binge drinking days increased the odds of same day MA use by 4.22 and 4.50 times, respectively (ps<0.0001). Further, binge drinking incrementally increased risk for MA use above and beyond the effects of drinking itself (p<0.0001). Lagged models revealed previous day MA use to predict following day MA use (p<0.0001), yet, after controlling for this relationship, neither previous day alcohol use nor previous day binge drinking predicted following-day MA use. Finally, the effect of binge drinking on MA use was stronger among individuals with lower MA dependence severity or higher alcohol problem severity (ps<0.05). CONCLUSIONS These results suggest that alcohol and MA are co-used in predictable patterns, and in particular, that binge drinking may be incrementally associated with the likelihood of MA use. Future studies are needed to explore the temporal relationship between alcohol and MA use within a given episode.

Modeling Alcohol Use Disorder Severity: An Integrative Structural Equation Modeling Approach

Background: Alcohol dependence is a complex psychological disorder whose phenomenology changes as the disorder progresses. Neuroscience has provided a variety of theories and evidence for the development, maintenance, and severity of addiction; however, clinically, it has been difficult to evaluate alcohol use disorder (AUD) severity. Objective: This study seeks to evaluate and validate a data-driven approach to capturing alcohol severity in a community sample. Method: Participants were non-treatment seeking problem drinkers (n = 283). A structural equation modeling approach was used to (a) verify the latent factor structure of the indices of AUD severity; and (b) test the relationship between the AUD severity factor and measures of alcohol use, affective symptoms, and motivation to change drinking. Results: The model was found to fit well, with all chosen indices of AUD severity loading significantly and positively onto the severity factor. In addition, the paths from the alcohol use, motivation, and affective factors accounted for 68% of the variance in AUD severity. Greater AUD severity was associated with greater alcohol use, increased affective symptoms, and higher motivation to change. Conclusion: Unlike the categorical diagnostic criteria, the AUD severity factor is comprised of multiple quantitative dimensions of impairment observed across the progression of the disorder. The AUD severity factor was validated by testing it in relation to other outcomes such as alcohol use, affective symptoms, and motivation for change. Clinically, this approach to AUD severity can be used to inform treatment planning and ultimately to improve outcomes.

Sex Differences in the Association Between Internalizing Symptoms and Craving in Methamphetamine Users.

Objectives:Methamphetamine (MA) users often have substantial psychiatric comorbidities, with nearly a third reporting lifetime mood disorders and over a quarter reporting lifetime anxiety disorders. Female MA users are more likely to endorse depression and anxiety symptoms compared with men. Craving has been related to mood/anxiety symptoms in MA users. To extend the literature on sex differences in MA use disorder, the present study examines the role of sex as a moderator of the relationship between mood/anxiety symptoms and MA craving. Methods:Participants (N = 203) were nontreatment-seeking, current MA users, recruited from the Los Angeles community for enrollment in a larger pharmacotherapy trial. At the assessment visit, participants completed multiple measures including the Methamphetamine Urge Questionnaire, the Beck Depression Inventory, and the Beck Anxiety Inventory. Results:The relationship between depression symptomatology and MA craving was moderated by sex (F = 6.18, P = 0.01), such that the relationship was positive and significant for men (P < 0.001), but was not significant for women. Similarly, sex significantly moderated the relationship between anxiety and MA craving (F = 5.99, P = 0.02), such that the relationship was also positive and significant in men, but not in women (P < 0.001). Conclusions:These results suggest that men may be more sensitive to the effects of internalizing symptoms on MA craving than women. Given cravings propensity to predict relapse, these initial findings indicate the necessity of treating comorbid psychiatric problems in male MA users, which may in turn assist in the attenuation of craving.

A Brief Smoking Cessation Intervention for Heavy Drinking Smokers: Treatment Feasibility and Acceptability

Approximately 20–25% of regular smokers report heavy drinking. Abstinent smokers are five times as likely to experience a smoking lapse during drinking episodes. Current efforts seek to improve treatments for this subgroup of heavy-drinking smokers. This study tested the feasibility and acceptability of addressing alcohol use in a brief, single session smoking cessation intervention (SMK+A) compared to smoking cessation counseling only (SMK); these interventions were grounded in a motivational interview framework and included personalized feedback, decisional balance, quit day setting, and tailored skills building (e.g., breathing techniques, coping with urges, dealing with social pressures) to maintain abstinence. Descriptive outcomes included reported helpfulness of intervention skills, readiness to change scores, and feasibility of participant recruitment and retention. We also assessed 7-day point prevalence of smoking cessation, and smoking and drinking reduction at 1-month follow-up. Participants (N = 22) were community-based treatment-seeking daily smokers (≥5 cigarettes/day) who were also heavy drinkers (≥14 drinks/week for men, ≥ 7 drinks/week for women; or ≥5 drinks on one episode in past week for men, ≥4 for women). Twenty five percent of interested individuals were eligible after initial phone screen, and all randomized participants were retained through follow up. All skills demonstrated high acceptability (i.e., rated between moderately and very helpful), and a significant proportion of participants in each condition reported taking action to reduce cigarette smoking and/or alcohol use at 1-month post-quit. Three participants in each condition (27.3%) attained bioverified (CO ≤ 4 parts per million and cotinine ≤ 3 ng/mL) smoking quit at follow-up. Given the modified interventions acceptability and flexibility, larger studies may help to elucidate this interventions effects on readiness to change, smoking cessation, and alcohol reduction.

The relationship between impulsivity and methamphetamine use severity in a community sample

BACKGROUND Abuse of psychostimulants, including methamphetamine (MA), has been linked to heightened impulsivity. While previous research has demonstrated differences in impulsivity between MA users and non-substance users, less is known about variability in impulsivity within MA users and whether the severity of MA use related problems predicts impulsivity within individuals who regularly use MA. This study aims to elucidate the relationship between impulsivity and MA use severity. METHOD Non-treatment seeking individuals who reported regular MA use (n = 177) completed an impulsivity battery comprising self-report and behavioral measures. A structural equation modeling (SEM) approach was used to test the relationship between the MA use related problem severity and measures of impulsivity. RESULTS The final SEM model of impulsivity and MA use related problems (CFI = 0.897, RMSEA = 0.059, S-B scaled χ2 [260,n = 103] = 406.86) revealed that greater MA use severity was associated with greater self-reported impulsiveness, but no relationship was found between MA use severity and behavioral measures of impulsivity. CONCLUSIONS The current findings extend previous research by providing additional evidence that MA use is associated with increased self-reported impulsivity and highlights the importance of evaluating impulsivity as a multidimensional construct.