Eric T. Moolchan

Behavioral and Neural Consequences of Prenatal Exposure to Nicotine

OBJECTIVE To review evidence for the neurodevelopmental effects of in utero exposure to nicotine. Concerns about long-term cognitive and behavioral effects of prenatal exposure to nicotine arise from reports of increased rates of disruptive behavioral disorders in children whose mothers smoked during pregnancy. The relatively high rate of tobacco smoking among pregnant women (25% of all pregnancies in the U.S.) underlines the seriousness of these concerns. METHOD This review examines the largest and most recent epidemiological and clinical studies that investigated the association of prenatal nicotine exposure with health, behavioral, and cognitive problems. Because of the numerous potential confounding variables in human research, findings from animal studies, in which environmental factors are strictly controlled, are also discussed. Finally, neural and molecular mechanisms that are likely to underlie neurodevelopmental disruptions produced by prenatal nicotine exposure are outlined. RESULTS A dose-response relationship between maternal smoking rates and low birth weight (potentially associated with lower cognitive ability) and spontaneous abortion is consistently found, whereas long-term developmental and behavioral effects in the offspring are still controversial, perhaps because of the difficulty of separating them from other genetic and environmental factors. Despite the wide variability of experimental paradigms used in animal studies, common physical and behavioral effects of prenatal exposure to nicotine have been observed, including low birth weight, enhanced locomotor activity, and cognitive impairment. Finally, disturbances in neuronal pathfinding, abnormalities in cell proliferation and differentiation, and disruptions in the development of the cholinergic and catecholaminergic systems all have been reported in molecular animal studies of in utero exposure to nicotine. CONCLUSIONS Prenatal exposure to nicotine may lead to dysregulation in neurodevelopment and can indicate higher risk for psychiatric problems, including substance abuse. Knowledge of prenatal exposure to nicotine should prompt child psychiatrists to closely monitor at-risk patients.

Methamphetamine and Amphetamine Pharmacokinetics in Oral Fluid and Plasma after Controlled Oral Methamphetamine Administration to Human Volunteers

BACKGROUND Methamphetamine (METH) and amphetamine (AMP) concentrations in 200 plasma and 590 oral fluid specimens were used to evaluate METH pharmacokinetics and pharmacodynamics after oral administration of sustained-release METH. METHODS Eight participants received four oral 10-mg S-(+)-METH hydrochloride sustained-release tablets within 7 days. Three weeks later, five participants received four oral 20-mg doses. Blood samples were collected for up to 24 h and oral fluid for up to 72 h after drug administration. RESULTS After the first oral dose, initial plasma METH detection was within 0.25-2 h; c(max) was 14.5-33.8 micro g/L (10 mg) and 26.2-44.3 micro g/L (20 mg) within 2-12 h. In oral fluid, METH was detected as early as 0.08-2 h; c(max) was 24.7-312.2 micro g/L (10 mg) and 75.3-321.7 micro g/L (20 mg) and occurred at 2-12 h. The median oral fluid-plasma METH concentration ratio was 2.0 across 24 h and was highly variable. Neutral cotton swab collection yielded significantly higher METH and AMP concentrations than citric acid candy-stimulated expectoration. Mean (SD) areas under the curve for AMP were 21% +/- 25% and 24% +/- 11% of those observed for METH in plasma and oral fluid, respectively. After a single low or high dose, plasma METH was >2.5 micro g/L for up to 24 h in 9 of 12 individuals (mean, 7.3 +/- 5.5 micro g/L at 24 h); in oral fluid the detection window was at least 24 h (mean, 18.8 +/- 18.0 micro g/L at 24 h). The plasma and oral fluid 24-h METH detection rates were 54% and 60%, respectively. After four administrations, METH was measurable for 36-72 h (mean, 58.3 +/- 14.5 h). CONCLUSIONS Perceived advantages of oral fluid for verifying METH exposure compared with urine include simpler specimen collection and reduced potential for adulteration, but urine offers higher analyte concentrations and a greater window of detection.

Safety and Efficacy of the Nicotine Patch and Gum for the Treatment of Adolescent Tobacco Addiction

Objectives. To determine the safety and efficacy of the nicotine patch and gum for adolescents who want to quit smoking. Design. Double-blind, double-dummy, randomized, 3-arm trial with a nicotine patch (21 mg), nicotine gum (2 and 4 mg), or a placebo patch and gum; all participants received cognitive-behavioral group therapy. Setting. Inner-city, outpatient clinic on the East Coast. Subjects. Thirteen- to 17-year-old adolescents who smoked ≥10 cigarettes per day (CPD), scored ≥5 on the Fagerström Test of Nicotine Dependence, and were motivated to quit smoking. Intervention. Twelve weeks of nicotine patch or gum therapy with cognitive-behavioral therapy, with a follow-up visit at 6 months (3 months after the end of treatment). Main Outcome Measures. Safety assessed on the basis of adverse event reports for all 3 groups, prolonged abstinence, assessed through self-report and verified with exhaled carbon monoxide (CO) levels of ≤6 ppm, in intent-to-treat analyses, and smoking reduction (CPD and thiocyanate concentrations) among trial completers. Results. A total of 120 participants were randomized (72% white, 70% female; age: 15.2 ± 1.33 years; smoking: 18.8 ± 8.56 CPD; Fagerström Test of Nicotine Dependence score: 7.04 ± 1.29) from 1999 to 2003. Participants started smoking at 11.2 ± 1.98 years of age and had been smoking daily for 2.66 ± 1.56 years; 75% had at least 1 current psychiatric diagnosis. Mean compliance across groups was higher for the patch (mean: 78.4–82.8%) than for the gum (mean: 38.5–50.7%). Both the patch and gum were well tolerated, and adverse events were similar to those reported in adult trials. Changes in mean saliva cotinine concentrations throughout treatment were not statistically significant. Intent-to-treat analyses of all randomized participants showed CO-confirmed prolonged abstinence rates of 18% for the active-patch group, 6.5% for the active-gum group, and 2.5% for the placebo group; the difference between the active-patch and placebo arms was statistically significant. There was no significant effect of patch versus gum or gum versus placebo on cessation outcomes. Abstinence rates at the 3-month follow-up assessment were sustained but were not significantly associated with treatment group. Mean smoking rates, but not CO or thiocyanate concentrations, decreased significantly in all 3 arms but not as a function of treatment group. Conclusions. Nicotine patch therapy combined with cognitive-behavioral intervention was effective, compared with placebo, for treatment of tobacco dependence among adolescent smokers. Decreases in the numbers of cigarettes smoked appeared to be offset by compensatory smoking. Additional study of nicotine gum, with enhanced instructional support, is needed to assess its efficacy among adolescent smokers.

A Review of Tobacco Smoking in Adolescents: Treatment Implications

OBJECTIVE To review current data on the tobacco epidemic in adolescents that impact treatment decisions. METHOD Epidemiological and pharmacological data, risk factors, characteristics of nicotine use in adolescents, and treatment intervention reports from the literature are discussed. RESULTS Of students in grades 9 to 12, 42.7% have used tobacco; 75% of teenage smokers will smoke as adults. Environmental and biological factors influence adolescent smoking, including sociodevelopmental aspects of adolescence, psychiatric history, genetic background, ethnic and gender characteristics, drug effects, and regulatory factors. Criteria for nicotine dependence are currently based on the experience with adult smokers. Overall, smoking cessation treatment for adolescents has been disappointing because of low participation, high attrition, and low quit rates. CONCLUSION Characterization of nicotine dependence and further assessment of the safety and efficacy of pharmacological treatment interventions in adolescents are needed given the formidable challenge of the tobacco epidemic in adolescents.

Behavioral Predictors of Substance-Use Initiation in Adolescents With and Without Attention-Deficit/Hyperactivity Disorder

OBJECTIVE. Our goal was to examine substance-use initiation in healthy adolescents and in adolescents who have been diagnosed with attention-deficit/hyperactivity disorder. METHODS. Seventy-eight adolescents (28 healthy and 50 with attention-deficit/hyperactivity disorder) participated in an ongoing longitudinal study of predictors of substance use. The substances most commonly reported were tobacco, alcohol, and marijuana. Aggression, conduct problems, hyperactivity, impulsivity, inattention, anxiety/depression, social difficulties, and somatic complaints were assessed at study entry and tested as predictors for later substance use. RESULTS. With an average of 4 years into the study, 37 adolescents had not used any substances, 41 had experimented with at least 1 substance, and 29 experimented with >1 substance. Psychiatric diagnoses (attention-deficit/hyperactivity disorder, attention-deficit/hyperactivity disorder and conduct disorder, and attention-deficit/hyperactivity disorder and depression/anxiety) did not influence reports of substance use. Distinct behavioral measures collected at study entry predicted use of different substances. In a multivariate analysis, aggression had the greatest association with tobacco smoking and marijuana use. Impulsivity was associated with alcohol use. Severity of drug exposure, indexed by the number of substances used, was predicted by aggression. CONCLUSIONS. This 4-year longitudinal study captured the onset of substance use, not abuse. Behavioral predictors differed with the type of substance used. These behavioral characteristics may raise suspicion among pediatricians for enhanced risk for substance-use initiation.

Dose-Related Enhancement of Mood and Cognition in Smokers Administered Nicotine Nasal Spray

The discovery of the role of nicotinic receptors in attention and memory has led to the testing of nicotinic analogs as cognitive enhancing agents in patient populations. Empirical information about nicotines ability to enhance elements of attention and memory in normal individuals might guide development of therapeutic uses of nicotine in cognitively impaired populations. The purpose of this study was to determine the effect of nicotine on continuous attention, working memory, and computational processing in tobacco-deprived and nondeprived smokers. A total of 28 smokers (14 men, 14 women) participated in a double-blind, placebo-controlled, within-subject study, in which they were overnight (12 h) tobacco deprived at one session and smoked ad libitum before the other session. At each session, participants received 0, 1, and 2 mg nicotine via nasal spray in random order at 90 min intervals. Before and after each dose, a battery of cognitive, subjective, and physiological measures was administered, and blood samples were taken for plasma nicotine concentration. Overnight tobacco deprivation resulted in impaired functioning on all cognitive tests and increased self-reports of tobacco craving and negative mood; nicotine normalized these deficits. In the nondeprived condition, nicotine enhanced performance on the continuous performance test (CPT) and an arithmetic test in a dose-related manner, but had no effect on working memory. In general, women were more sensitive than men to the subjective effects of nicotine. These results provide an unequivocal determination that nicotine enhanced attentional and computational abilities in nondeprived smokers and suggest these cognitive domains as substrates for novel therapeutic indications.

Gender Differences in Acute Tobacco Withdrawal: Effects on Subjective, Cognitive, and Physiological Measures

Gender differences in tobacco withdrawal are of considerable clinical importance, but research findings on this topic have been mixed. Methodological variation in samples sizes, experimental design, and measures across studies may explain the inconsistent results. The current study examined whether male (n = 101) and female (n = 102) smokers (> or =15 cigarettes/day) differed in abstinence-induced changes on a battery of self-report measures (withdrawal, affect, craving), cognitive performance tasks (attention, psychomotor performance), and physiological responses (heart rate, blood pressure, brain electroencephalogram). Participants attended 2 counterbalanced laboratory sessions, 1 following 12 hr of abstinence and the other following ad libitum smoking. Results showed that women reported greater abstinence-induced increases in negative affect, withdrawal-related distress, and urge to smoke to relieve withdrawal distress. In contrast, both genders reported similar abstinence-induced changes in positive affect and urge to smoke for pleasure. Men and women exhibited generally similar abstinence-induced changes in physiological and cognitive performance measures. In addition, gender did not moderate the association between withdrawal symptoms and baseline measures of smoking behavior and dependence. Abstinence-induced changes in withdrawal distress mediated the effect of gender on latency until the 1st cigarette of the day at trend levels ( p < .10). These findings suggest that there are qualitative gender differences in the acute tobacco withdrawal syndrome that may underlie gender-specific smoking patterns.

Smoking topography: Reliability and validity in dependent smokers

Data from two studies were analyzed to determine whether smoking through the mouthpiece of a topography unit yields consistent measures over time and to verify that smoking through a mouthpiece results in a similar degree of smoke exposure as conventional smoking. In both studies, subjects smoked their usual brand of cigarette ad libitum. In study A, subjects (n=7) smoked through a mouthpiece on 4 separate experimental days. In study B, subjects (n=10) smoked on 2 separate days: Once conventionally and once through a mouthpiece. In both studies, exhaled carbon monoxide (CO) and physiological effects (heart rate and blood pressure) were measured before and after smoking. In study B, plasma nicotine concentrations also were measured. In study A, puff volume, puff duration, interpuff interval, and maximum puff velocity averaged 30.8 ml,.9 s, 19.9 s, and 44.6 ml/s, respectively. Intraclass correlation coefficients computed for puff volume (0.66), puff duration (0.75), and maximum puff velocity (0.68) indicated that these measures showed good reliability. In study B, smoking through the mouthpiece yielded similar topographical (time to smoke and number of puffs per cigarette) measures as conventional smoking. Also similar were changes in biochemical values: Plasma nicotine (18.5 ng/ml vs. 25.5 ng/ml), exhaled CO (4.6 ppm vs. 5.1 ppm), and heart rate (8.6 beats/min vs. 7.4 beats/min) for conventional and topography mouthpiece smoking conditions, respectively. Topography measures did not differ significantly between the two studies. Overall, the data from these two small-sample studies suggest that smoking topography provides a valid and reliable index of conventional smoking and an indirect measure of smoke exposure.

Tobacco Craving Questionnaire: Reliability and validity of a new multifactorial instrument

This study documented the initial reliability and validity of the Tobacco Craving Questionnaire (TCQ), a new multidimensional questionnaire to assess tobacco craving. Current cigarette smokers (n=213) not attempting to reduce or quit smoking completed the 47-item TCQ and other forms assessing demographics, tobacco and other drug use history, quit attempts, and current mood. Exploratory factor analyses and structural equation modeling indicated that a four-factor solution best described the item structure. Factor subscales derived from the 17 items with significant loadings had low to high internal consistencies and interitem correlations and exhibited low to moderate, positive intercorrelations. Factor scales were significantly correlated with single-item measures of craving, current mood, and daily cigarette smoking. Results indicated that four specific constructs characterized craving for tobacco: (a) Emotionality, or smoking in anticipation of relief from withdrawal symptoms or negative mood, (b) expectancy, or anticipation of positive outcomes from smoking, (c) compulsivity, or an inability to control tobacco use, and (d) purposefulness, or intention and planning to smoke for positive outcomes. These preliminary data suggest that the TCQ is a reliable and valid instrument for assessing tobacco craving in individuals not attempting to reduce or quit smoking.

Tobacco craving: Intensity-related effects of imagery scripts in drug abusers.

Two experiments were conducted to determine whether active imagery would elicit tobacco craving in smokers with histories of drug abuse who were not interested in quitting smoking. In Experiment 1, the authors used scripts that contained positive, negative, or neutral affective content with and without descriptions of smoking urge. Scripts with urge content and negative affect scripts increased subjective reports of tobacco craving. An interaction between affective manipulation and urge content was observed on self-reported mood. In Experiment 2, positive affect scripts that varied in amount of urge content produced an orderly increase in tobacco craving as a function of urge intensity, suggesting that changes were specific to the imagery manipulation. In both experiments, increases in tobacco craving were positively correlated with craving for drug of choice, suggesting that stimuli that engender smoking urges may occasion craving for other drugs of abuse.