Stephen J. Heishman

Smoking History and Nicotine Effects on Cognitive Performance

This study examined the effects of abstinence from smoking, of smoking history, and of nicotine administration on visual attention (2-Letter Search Task), verbal information processing (Logical Reasoning Task), and working memory (N-Back Tasks). Fourteen smokers, 15 ex-smokers, and 9 never-smokers took part. All subjects participated in a training session (when smokers had been smoking ad libitum) and in two subsequent test sessions after administration of 4 mg nicotine gum or placebo, respectively. Smokers were 12-h abstinent when they received gum. An effect of acute nicotine administration (independent of smoking history) was seen only with respect to reaction time on the 2-Letter Search Task. Working memory performance was related to smoking history (smokers performed most poorly and never-smokers best). The Logical Reasoning Task showed no effects of either acute or chronic nicotine exposure. The findings indicate that nicotine may influence focusing of attention in smokers as well as nonsmokers, and that trait-like differences in some cognitive domains, such as working memory, may be either long-term effects or etiological factors related to smoking.

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.

Effect of nicotine on brain activation during performance of a working memory task

Nicotine influences cognition and behavior, but the mechanisms by which these effects occur are unclear. By using positron emission tomography, we measured cognitive activation (increases in relative regional cerebral blood flow) during a working memory task [2-back task (2BT)] in 11 abstinent smokers and 11 ex-smokers. Assays were performed both after administration of placebo gum and 4-mg nicotine gum. Performance on the 2BT did not differ between groups in either condition, and the pattern of brain activation by the 2BT was consistent with reports in the literature. However, in the placebo condition, activation in ex-smokers predominated in the left hemisphere, whereas in smokers, it occurred in the right hemisphere. When nicotine was administered, activation was reduced in smokers but enhanced in ex-smokers. The lateralization of activation as a function of nicotine dependence suggests that chronic exposure to nicotine or withdrawal from nicotine affects cognitive strategies used to perform the memory task. Furthermore, the lack of enhancement of activation after nicotine administration in smokers likely reflects tolerance.

Acute and residual effects of marijuana profiles of plasma thc levels physiological subjective and performance measures

Three experienced marijuana smokers participated in four 2-day experimental sessions in which they smoked either 0, 1, or 2 marijuana cigarettes containing 2.57% delta 9-tetrahydrocannabinol (THC) at two different times on the first day. A battery of physiological, subjective, and performance measures was repeated throughout day 1 to assess acute effects and on day 2 to measure any residual effects of marijuana. Blood samples were also repeatedly collected to examine the relationship between plasma levels and pharmacological effects of THC. Acutely, marijuana increased heart rate and subjective ratings of drug effects and slightly impaired performance on a circular lights task in all subjects. Performance was also impaired (decreased accuracy and increased response time) on serial addition/subtraction and digit recall tasks on day 1 in two subjects. On day 2, tachycardia and subjective effects of marijuana were not observed. Performance remained impaired on the arithmetic and recall tasks on day 2, although the decrements were not as large as those observed on day 1. In general, plasma THC levels covaried with the other measures. These preliminary results suggest that marijuana can adversely affect complex human performance up to 24 hours after smoking.

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.

Cannabis Withdrawal Among Non-Treatment-Seeking Adult Cannabis Users

This study investigates the clinical significance of a cannabis withdrawal syndrome in 104 adult, non-treatment-seeking, primarily cannabis users who reported at least one serious attempt to stop using cannabis. Retrospective self-report data were obtained on eighteen potential cannabis withdrawal symptoms derived from the literature, including co-occurrence, time course, and any actions taken to relieve the symptom. Study findings provide evidence for the clinical significance of a cannabis withdrawal syndrome, based on the high prevalence and co-occurrence of multiple symptoms that follow a consistent time course and that prompt action by the subjects to obtain relief, including serving as negative reinforcement for cannabis use.

Behavioral and cognitive effects of smoking: Relationship to nicotine addiction

Nicotine addiction is an extremely complex process that involves biological, psychological, behavioral, and cultural factors. Three factors that influence smoking and that are influenced by smoking are performance, stress, and body weight. We know that if nicotine-addicted smokers are deprived of nicotine, attentional and cognitive abilities can be impaired, and such deficits can be reversed if the person smokes or is given nicotine. In nonsmokers and nondeprived smokers, nicotine enhances finger tapping, focused and sustained attention, recognition memory, and reasoning. Stress results in increased smoking, but there is little empirical evidence that smoking reduces stress. Stress reduction from smoking is likely the relief of withdrawal-induced negative mood that is experienced between cigarettes. Smokers weigh on average 3-4 kg less than nonsmokers, and the weight-gain seen after quitting smoking also averages 3-4 kg. Changes in eating and energy expenditure are responsible for the body weight changes seen during smoking cessation and relapse. We need to know the full range of conditions under which nicotine affects behavior. The mechanisms by which stress functions to maintain nicotine addiction are not well understood. We do not know what interventions are effective in addressing the stress experienced during smoking cessation. Because no effective interventions have been developed to prevent weight-gain after quitting, research should focus on the concern or perception of weight-gain. We need to understand how and why body weight concerns vary across gender, age, and ethnicity because of the implications for designing effective smoking-cessation programs.

Acute and residual effects of marijuana in humans.

Marijuana continues to be the most commonly abused illicit drug in the United States. Because many people abuse marijuana during the evening and on weekends and then go to work or school the next day, more research is needed on the residual effects of marijuana. The current study sought to examine both acute and residual subjective. physiologic, and performance effects of smoking a single marijuana cigarette. Ten healthy male volunteers who reported recent use of marijuana resided on a residential research ward. On three separate days, subjects smoked one NIDA marijuana cigarette containing either 0%, 1.8%, or 3.6% delta9-tetrahydrocannabinol (THC) according to a paced puffing procedure. Subjective, physiologic, and performance measures were collected prior to smoking, five times following smoking on that day, and three times on the following morning. Subjects reported robust subjective effects following both active doses of marijuana, which returned to baseline levels within 3.5 h. Heart rate increased and the pupillary light reflex decreased following active dose administration with return to baseline on that day. A new finding was that marijuana smoking acutely produced decrements in smooth pursuit eye tracking. Although robust acute effects of marijuana were found on subjective and physiological measures, and on smooth pursuit eye tracking performance, no effects were evident the day following administration, indicating that the residual effects of smoking a single marijuana cigarette are minimal.

An open-label study of a functional opioid κ antagonist in the treatment of opioid dependence

Several lines of evidence, including the well-established observation that kappa opiate agonists produce dysphoria and psychotomimetic effects in humans, suggest that dysfunction of the endogenous kappa opioid system may contribute to opioid and cocaine addiction. The objective of this open-label study was to determine the effectiveness of a functional kappa antagonist as a treatment for opioid dependence. This was accomplished by combining a partial mu agonist/kappa antagonist (buprenorphine, 4 mg, sublingual) with a mu antagonist (naltrexone, 50 mg by mouth), theoretically leaving kappa antagonism as the major medication effect. Subjects were treatment-seeking heroin-dependent (as per Diagnostic and Statistical Manual of Mental Disorders, 4th ed.) men (41 +/- 7 years old; 19 +/- 8 years heroin use) eligible for methadone maintenance. After inpatient detoxification and a naloxone-challenge test to verify that they were not physically dependent on opioids, subjects received naltrexone. Starting on the fourth day, patients also received liquid buprenorphine. All patients received medication at the clinic 6 days per week and a full program of psychosocial treatment. The major endpoints of the study were: pupil diameter to determine if the mu agonist effects of buprenorphine were blocked by naltrexone, urine toxicology, and retention in treatment. Five patients (33%) completed the 3-month study. Four were abstinent from opioids and cocaine for the entire study, and one was abstinent from opioids and cocaine for the last 9 weeks. Six subjects dropped out due to either minor side effects or disliking the sensation of sublingual buprenorphine. There were no significant changes in pupillary diameter. The positive response to treatment exceeds that expected from naltrexone alone (90% dropout). These promising results suggest that controlled studies of this medication combination should be conducted.

Tobacco, cocaine, and heroin: Craving and use during daily life.

BACKGROUND Relationships among tobacco smoking, tobacco craving, and other drug use and craving may have treatment implications in polydrug-dependent individuals. METHODS We conducted the first ecological momentary assessment (EMA) study to investigate how smoking is related to other drug use and craving during daily life. For up to 20 weeks, 106 methadone-maintained outpatients carried PalmPilots (PDAs). They reported their craving, mood, behaviors, environment, and cigarette-smoking status in 2 to 5 random-prompt entries/day and initiated PDA entries when they used cocaine or heroin or had a discrete episode of craving for cocaine or heroin. RESULTS Smoking frequency increased linearly with random-prompt ratings of tobacco craving, cocaine craving, and craving for both cocaine and heroin. Smoking frequency was greater during discrete episodes of cocaine use and craving than during random-prompt reports of low craving for cocaine. This pattern was also significant for dual cocaine and heroin use and craving. Smoking and tobacco craving were each considerably reduced during periods of urine-verified abstinence from cocaine, and there was a (nonsignificant) tendency for morning smoking to be especially reduced during those periods. CONCLUSIONS This EMA study confirms that smoking and tobacco craving are strongly associated with the use of and craving for cocaine and heroin. Together with prior findings, our data suggest that tobacco and cocaine may each increase craving for (and likelihood of continued use of) themselves and each other. Treatment for tobacco dependence should probably be offered concurrently with (rather than only after) initiation of treatment for other substance-use disorders.