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.

Marijuana Craving Questionnaire: development and initial validation of a self-report instrument.

AIMS: To develop and validate a multi-dimensional questionnaire on marijuana craving. DESIGN AND MEASUREMENTS: Current marijuana smokers (n = 217) not seeking treatment completed a 47-item Marijuana Craving Questionnaire (MCQ) and forms assessing demographics, drug use history, marijuana quit attempts and current mood. FINDINGS: Exploratory and confirmatory factor analyses indicated that a four-factor solution best described the item structure. Factor subscales derived from the 17 items with significant loadings had respectable internal consistencies and were stable across settings and subgroups. The subscales exhibited low to moderate, positive intercorrelations and were significantly correlated with marijuana use history and a wide range of single-item measures of craving. CONCLUSIONS: Findings suggested that four specific constructs characterize craving for marijuana: (1) compulsivity, an inability to control marijuana use; (2) emotionality, use of marijuana in anticipation of relief from withdrawal or negative mood; (3) expectancy, anticipation of positive outcomes from smoking marijuana; and (4) purposefulness, intention and planning to use marijuana for positive outcomes. These data indicate that the MCQ is a valid and reliable instrument for assessing marijuana craving in individuals not seeking drug abuse treatment and that marijuana craving can be measured in the absence of withdrawal.

A factor analysis of the fagerstrom tolerance questionnaire.

A factor analysis of 1309 Fagerstrom Tolerance Questionnaires (FTQ) was performed with LISCOMP software, which utilizes tetrachoric correlations to account for the dichotomous responses of the FTQ. Three factors with eigenvalues greater than 1.0 were obtained, accounting for 56.6% of the variance. Factor 1 was loaded by questions "How soon on waking do you smoke your first cigarette?," "Do you find it difficult to refrain from smoking in places it is forbidden?," "How many cigarettes a day do you smoke?," and "Do you smoke if you are so ill that you are in bed most of the day?" Factor 2 was loaded by questions "Which cigarette would you hate to give up?" and "Do you smoke more during the morning than during the rest of the day?" Factor 3 was loaded exclusively by question "What brand do you smoke?" The question "Do you inhale always, sometimes, or never?" loaded exclusively on a fourth factor, however its eigenvalue did not reach significance. Support is provided for the modification of the eight-item FTQ to the six-item Fagerstrom Test for Nicotine Dependence (FTND). Based on the wording of the questions that loaded on each factor, we propose that Factor 2 assesses the degree of urgency to initiate smoking after overnight abstinence and that Factor 1 reflects the persistence of smoking during waking hours.

Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716.

BACKGROUND: SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta-9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans. METHODS: Sixty-three healthy men with a history of marijuana use were randomly assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo marijuana cigarette 2 hours later. Psychological effects associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration. RESULTS: Single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 90-mg dose produced 38% to 43% reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by all subjects. CONCLUSIONS: SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana.

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.

Tolerance to repeated nicotine administration on performance, subjective, and physiological responses in nonsmokers.

RATIONALE: When administered acutely to nonsmokers, nicotine's effects on performance are inconsistent, perhaps because of suboptimal dosing or initial dysphoria that could interfere with performance. OBJECTIVE: The purpose of this study was to determine if a range of nicotine doses administered for 8 days to nonsmokers would enhance psychomotor and cognitive abilities and to document the development of nicotine tolerance or sensitization. METHODS: Twelve male volunteers, who reported ever smoking five cigarettes or less, participated in 8 consecutive experimental days in which they were administered four doses of nicotine polacrilex gum each day in this order: 0, 2, 4, and 8 mg. Performance, subjective, and physiological measures were assessed before and after each dose. RESULTS: Plasma nicotine concentration ranged from 6.9 to 11.5 ng/ml following the 8 mg dose. Nicotine increased rate of responding and decreased response time on working memory (digit recall); however, accuracy was impaired. Nicotine also decreased accuracy on visual scanning and attention (two-letter search), and the 8 mg dose impaired gross motor coordination (circular lights). Tolerance did not develop to the performance impairing effects of nicotine. Nicotine produced dose-related increases in ratings of dysphoria and negative mood, including tension, anxiety, nervousness, turning of stomach, and sedation. Tolerance developed to some, but not all, of these aversive effects. Tolerance also was not observed to the increased cardiovascular measures. CONCLUSION: Although tolerance developed to some of the aversive effects of nicotine, performance enhancement was not observed. These data do not support the hypothesis that nicotine-induced performance enhancement contributes to the reinforcing effects of tobacco use during the early stages of dependence development.

Nalmefene: blockade of intravenous morphine challenge effects in opioid abusing humans.

No studies have assessed the dose-effect or duration of opioid blockade in opioid abusers produced by oral nalmefene, a micro-opioid antagonist. The present study examined the profile and time course of oral nalmefene blockade of subjective and physiological effects produced by intravenous morphine. To assess these effects, seven opioid abusers received oral nalmefene (0, 50 and 100 mg) followed by intravenous morphine (0, 10 and 20 mg) challenges every 24 h for 96 h using a Latin square randomized cross-over design. The duration of blockade varied by measure and dose. Both 50 and 100 mg nalmefene blocked morphine's effects up to 48 h.

An open-label study of a functional opioid kappa 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 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.

Reinforcing and subjective effects of morphine in human opioid abusers: effect of dose and alternative reinforcer.

RATIONALE: Although most opioid self-administration research has been conducted with laboratory animals, such research with humans is necessary to answer questions unique to human drug-taking behavior. OBJECTIVE: We investigated the influence of morphine dose and an alternative non-drug reinforcer on choice between morphine versus money and examined the relationship between drug-reinforced behavior and subjective euphoria. METHODS: Five male opioid users participated in the 7-week study. During the first 5 weeks, a single dose of morphine (0, 4, 8, 16, or 32 mg/70 kg) was available each week. On Monday, subjects received an IM injection of the dose tested that week. On Tuesday, Thursday, and Friday, subjects could work for morphine or money under a second-order, progressive ratio schedule. For each primary ratio completed on the drug lever, subjects earned one-ninth of the available drug dose, and for each ratio completed on the money lever, subjects earned $1. Total amount of drug earned was administered in a single IM injection at the end of the session; money earned was credited to the subject's account. RESULTS: As morphine dose increased, responding for drug increased in an orderly manner and responding for money decreased. During the final phase of the study, the lowest and highest doses that maintained drug responding for each subject were repeated, and the value of the alternative reinforcer was increased to $2 per ratio. This manipulation was associated with decreased drug-maintained responding at the lowest, but not the highest, reinforcing dose of morphine. CONCLUSION: The progressive ratio, concurrent access procedure may be useful in predicting the outcome of drug abuse treatment interventions that use alternate reinforcement strategies.

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.

Smoking after nicotine deprivation enhances cognitive performance and decreases tobacco craving in drug abusers.

This study investigated the effects of nicotine deprivation and smoking on cognitive abilities and tobacco craving. Twenty smokers with histories of drug abuse completed the Questionnaire on Smoking Urges (QSU) and two cognitive tests before and after smoking two cigarettes during two 90-min sessions. After two cigarettes were smoked at Session 1, subjects were tobacco abstinent for 18 h until Session 2 the next morning. Response time on a logical reasoning test was unchanged by tobacco deprivation and was faster after smoking on Session 2. Deprivation slowed responding on a letter search test, which was reversed by smoking to pre-deprivation baseline. Tobacco deprivation increased scores on the QSU; smoking after deprivation reduced craving scores to smoking baseline levels. These results confirmed the utility of the QSU to measure changes in craving induced by tobacco deprivation and smoking. Further, the data suggest that deprivation-induced deficits and smoking-induced enhancements in performance may be specific to certain cognitive domains.

Laboratory validation study of drug evaluation and classification program: alprazolam, d-amphetamine, codeine, and marijuana.

The Drug Evaluation and Classification (DEC) program is used by police agencies to identify drivers impaired because of drug use and to determine the class(es) of drug causing the impairment. The primary goal of this study was to determine the validity of the DEC evaluation in predicting whether research volunteers were administered alprazolam, d-amphetamine, codeine, or marijuana. A secondary goal was to determine the accuracy of Drug Recognition Examiners (DREs) in detecting if subjects were dosed with these drugs. Community volunteers (n = 48) were administered alprazolam (0, 1, 2 mg), d-amphetamine (0, 12.5, 25 mg), codeine (0, 60, 120 mg), or marijuana (0, 3.58% THC) in a double-blind, randomized, between-subject design. A single drug dose or placebo was administered at each experimental session, and blood samples were obtained before and after dosing. With the exception of marijuana, plasma drug concentration was at or near maximum during the DEC evaluation. The ability of the DEC evaluation to predict the intake of alprazolam, d-amphetamine, codeine, or marijuana was optimal when using 2-7 variables from the evaluation. DREs' decisions of impairment were consistent with the administration of any active drug in 76% of cases, and their drug class decisions were consistent with toxicology in 32% of cases, according to standards of the International Association of Chiefs of Police. These findings suggest that the DEC evaluation can be used to predict accurately acute administration of alprazolam, d-amphetamine, codeine, and marijuana and that predictions of drug use may be improved by focusing on a subset of variables.

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.

Comparative effects of alcohol and marijuana on mood, memory, and performance.

This study compared subjective and behavioral effect profiles of alcohol and smoked marijuana using technology that controlled puffing and inhalation parameters. Male volunteers (n = 5) with histories of moderate alcohol and marijuana use were administered three doses of alcohol (0.25, 0.5, or 1.0 g/kg), three doses of marijuana [4.8, or 16 puffs of 3.55% delta 9-tetrahydrocannabinol (THC)], and placebo in random order under double blind conditions in seven separate sessions. Blood alcohol concentration (10-90 mg/dl) and THC levels (63-188 ng/ml) indicated that active drug was delivered to subjects dose dependently. Alcohol and marijuana produced dose-related changes in subjective measures of drug effect. Ratings of perceived impairment were identical for the high doses of alcohol and marijuana. Both drugs produced comparable impairment in digit-symbol substitution and word recall tests, but had no effect in time perception and reaction time tests. Alcohol, but not marijuana, slightly impaired performance in a number recognition test. These data are useful for understanding the relative performance impairment produced by alcohol and marijuana at the delivered doses and the relationship between their subjective and behavioral effects.

Society for Research on Nicotine and Tobacco.

The proceedings of the second annual scientific conference of the Society for Research on Nicotine and Tobacco are summarized. The goal of the annual conference was to disseminate information about ongoing nicotine research from biological, behavioral and social perspectives. Data were presented describing our current understanding of the structure and function of neuronal nicotinic acetylcholine receptors, by which nicotine exerts most, if not all, of its effects in the brain. The conformational complexity of receptor subunits expressed in different brain areas contributes significantly to the complexity of responses observed to nicotinic agonists. Nicotine is being developed as a medication that might be used to maintain smoking cessation and to treat various medical diseases. The potential toxicity of nicotine, apart from cigarette smoking, is an important variable in assessing the benefits and risks of such therapeutic applications. The risks of nicotine-containing medications appear to be far less than those associated with tobacco use. Recent data indicate that cigarette smoking is increasing among young in the United States. Adolescent smokers are interested in quitting and make frequent quit attempts, but are usually not successful. Effective methods are needed to manage adolescent smokers before they become heavily addicted. Nicotine replacement as a pharmacological treatment for smoking cessation has made a significant contribution in improving quit rates. New medications have been developed that target specific populations of smokers.

Laboratory validation study of drug evaluation and classification program: ethanol, cocaine, and marijuana.

The Drug Evaluation and Classification (DEC) program is used by police agencies to determine if individuals are behaviorally impaired because of drug use, and, if impaired, to determine the class of drug(s) causing the impairment. Although widely used, the validity of the DEC evaluation has not been rigorously tested. The primary goal of this study was to determine the validity of the variables of the DEC evaluation in predicting whether research volunteers had been administered ethanol, cocaine, or marijuana; a secondary goal was to determine the accuracy of trained police officers (Drug Recognition Examiner, DRE) in detecting whether subjects had been dosed with ethanol, cocaine, or marijuana. Community volunteers (n = 18) with histories of drug use received ethanol (0, 0.28, 0.52 g/kg), cocaine (4, 48, 96 mg/70 kg), and marijuana (0, 1.75, 3.55% THC) in a double-blind, randomized, within-subjects design. A single drug dose or placebo was administered during each of nine experimental sessions, and blood samples were obtained before and periodically after dosing. With the exception of marijuana, plasma drug concentration was at or near the observed maximum during the DEC evaluation. The ability of the DEC evaluation to predict the intake of ethanol, cocaine, or marijuana was optimal when using 17-28 variables from the evaluation. When DREs concluded impairment was due to drugs other than ethanol, their opinions were consistent with toxicology in 44% of cases. These findings suggest that the DEC evaluation can be used to predict accurately acute administration of ethanol, cocaine, or marijuana, and that predictions of drug use may be improved if DREs focused on a subset of variables.