Cigarette smoking and state-dependent memory

Two experiments were carried out to investigate whether cigarette smoking could produce state-dependent learning (SDL) in humans. The first experiment was concerned with the methodological issue of choosing an appropriate control cigarette for use in an SDL design. A low nicotine content (0.2 mg) cigarette was chosen as it did not appear to affect the physiological arousal of the subjects. In Experiment 2, it was shown that cigarette smoking can produce state-dependent memory effects. The most likely basis for the results is the arousal produced by the nicotine content of the cigarette.     

The effects of transdermal nicotine therapy for smoking cessation on depressive symptoms in patients with major depression.

This study examines the effects of transdermal nicotine patches for smoking cessation on depressive and withdrawal symptoms among 38 non-medicated subjects with Major Depressive Disorder. The study was conducted over a 29-day period, which included a 7 day baseline phase, a 14 day treatment phase, and an 8 day placebo phase. During the treatment phase subjects received either active nicotine patches (N = 18) or placebo patches (N = 20) that were administered in a randomized, double-blind fashion. The target quit date (TQD) was day 8. Significantly, more subjects in the placebo group than in the nicotine group resumed smoking following the TQD (50% vs. 22%). There was little evidence for effects of active nicotine patches on measures of mood (HRSD, BDI, POMS) or withdrawal symptoms among subjects that remained abstinent throughout the study (N = 24). Those who resumed smoking had more severe withdrawal symptoms than those who remained abstinent. One patient in the placebo group (n = 20) became more depressed after 2 weeks of abstinence. None of the patients in the nicotine group (n = 18) became more depressed.     

Naltrexone augments the effects of nicotine replacement therapy in female smokers

BACKGROUND: There is increased recognition that gender differences may influence outcomes and may modify vulnerability to tobacco addiction, severity of course and response to different treatments. We hypothesized that naltrexone, which has been used to successfully treat opioid and alcohol dependence, when combined with nicotine replacement therapy (NRT) and psychosocial therapy (PT) may enhance smoking cessation rates in women. METHODS: Forty-four adult female smokers meeting DSM-IV criteria for nicotine dependence with expired carbon monoxide content of > or = 15 ppm were randomly assigned in a double blind placebo controlled clinical trial of naltrexone 50 mg + NRT patch + psychosocial therapy (N + NRT + PT)(N = 12) or placebo + NRT patch + psychosocial therapy (P + N + PT)(N=12) for 12 weeks. RESULTS: Twelve weeks of treatment was completed by 54.5%. Smoking cessation among females who completed the 12 weeks for N + NRT + PT was 91.7% (11/12) and for P + NRT + PT was 50% (6/12). CONCLUSION: Naltrexone combined with NRT and psychosocial therapy appears to have a positive cessation effect on women and may be a new treatment option for recidivist female smokers.     

Nicotine replacement to reduce cigarette consumption in smokers who are unwilling to quit: a randomized trial

The objective of this study was to assess whether nicotine replacement therapy, administered in a real-life situation, could reduce cigarette consumption in smokers who were not prepared to quit smoking. Daily smokers of more than 20 cigarettes per day who had no intention to quit smoking in the next 6 months were recruited from the general population and randomly assigned to either a 6-month treatment of nicotine (choice among a 15-mg nicotine patch, a 4-mg nicotine gum, a 10-mg nicotine inhaler, or a combination of these, N = 265), matching placebo products (N = 269), or no intervention (N = 389). Products were sent to participants by mail. Education was limited to a booklet. Of 923 participants, 879 (95%) were followed up after 6 months. Mean baseline consumption was 30 cigarettes per day in all groups. At 6 months, cigarette consumption decreased by a median of 10 cigarettes per day in the nicotine group, 7.5 in the placebo group, and 2.5 among controls ( < 0.04 for all pair-wise comparisons). Smoking cessation rates were low (2%-4%) and did not differ significantly between groups. Quit attempts were less frequent among controls (21%) than among the nicotine (28%, = 0.04) and placebo (27%, = 0.08) subjects. In conclusion, nicotine replacement therapy helped smokers reduce their cigarette consumption and maintain this reduction over 6 months, but a large part of this reduction was attributable to a placebo effect. Nicotine treatment for smoking reduction had no detectable impact on smoking cessation.     

Time course of smoking withdrawal symptoms as a function of nicotine replacement

Subjects (N = 32) provided morning, afternoon, and evening data for week-1 withdrawal from smoking. Withdrawal symptoms were measured using Schneider's Smoker Complaint Scale. Twenty subjects received nicotine gum and 12 subjects received placebo gum. Carbon monoxide levels verified smoking abstinence. Results showed significantly less withdrawal for nicotine gum subjects compared to the placebo group. A significant treatment- x -time of day interaction was also observed: Placebo subjects reported increased withdrawal in the evenings compared to their morning and afternoon scores, and in contrast to nicotine-group responses. The results provide evidence for nicotine withdrawal and its alleviation by nicotine gum.     

A behavioural and functional neuroimaging investigation into the effects of nicotine on sensorimotor gating in healthy subjects and persons with schizophrenia

Rationale Schizophrenia patients display an excessive rate of smoking compared to the general population. Nicotine increases acoustic prepulse inhibition (PPI) in animals as well as healthy humans, suggesting that smoking may provide a way of restoring deficient sensorimotor gating in schizophrenia. No previous study has examined the neural mechanisms of the effect of nicotine on PPI in humans. Objectives To investigate whether nicotine enhances tactile PPI in healthy subjects and patients with schizophrenia employing a double-blind, placebo-controlled, cross-over design and, if so, what are the neural correlates of nicotine-induced modulation of PPI. Materials and methods In experiment 1, 12 healthy smokers, 12 healthy non-smokers and nine smoking schizophrenia patients underwent testing for tactile PPI on two occasions, 14 days apart, once after receiving (subcutaneously) 12 μg/kg body weight of nicotine and once after receiving saline (placebo). In experiment 2, six healthy subjects and five schizophrenia patients of the original sample (all male smokers) underwent functional magnetic resonance imaging (fMRI) under the same drug conditions and the same tactile PPI paradigm as in experiment 1. Results Nicotine enhanced PPI in both groups. A comparison of patterns of brain activation on nicotine vs placebo conditions showed increased activation of limbic regions and striatum in both groups after nicotine administration. Subsequent correlational analyses demonstrated that the PPI-enhancing effect of nicotine was related to increased hippocampal activity in both groups. Conclusions Nicotine enhances tactile PPI in both healthy and schizophrenia groups. Our preliminary fMRI findings reveal that this effect is modulated by increased limbic activity. Jeffrey A. Gray is deceased.     

Heavy nicotine and alcohol use in alcohol dependence is associated with D2 dopamine receptor (DRD2) polymorphism

Cigarette smoking in those who are alcohol dependent is associated with higher morbidity and mortality. The A1 allele of the D2 dopamine receptor (DRD2) gene has been independently associated with alcohol and nicotine dependence. Whether this polymorphism is associated with nicotine dependence in those who are also alcohol dependent has not been investigated. Subjects were 84 (61 males; 23 females) Caucasian DSM IV diagnosed nicotine- and alcohol-dependent subjects sampled from consecutive admissions to a hospital alcohol detoxification ward. Data were obtained through standardised measures of nicotine and alcohol consumption and dependence severity. A1+ allelic (A1/A1 or A1/A2 genotype) compared to A1- allelic (A2/A2 genotype only) patients were characterised by higher levels of alcohol and cigarette consumption. A1+ allelic patients reported greater alcohol dependence severity, but not nicotine dependence severity. When the combined nicotine and alcohol dose was examined, A1+ allelic patients consumed significantly more of these drugs than their A1- allelic counterparts.     

Effects of post-trial administration of nicotine on human memory: evaluating the conditions for improving memory

In the studies reported here, we investigated the effects of nicotine on memory for unrelated word lists. Nicotine was delivered through cigarette smoking, and memory performance was assessed using both intentional and incidental recall tasks, and employing an additional, indirect measure of memory. We report the results of four experiments in which we manipulated 1) the intake of nicotine using nicotine-containing and nicotine-free cigarettes, 2) the associative aspects of the word-sets, by unrelated words and category words and by instructing subjects to use an associative mnemonic strategy, 3) the opportunity for rehearsal between the presentation and recall, and 4) the time of nicotine administration, post- or pre-trial. We found a positive effect of post-trial nicotine on memory in the incidental recall task, as indicated by enhanced repetition priming, but no effect of nicotine on either immediate recall or pronunciation times (experiments 1 and 2). In experiment 3 we examined the effects of post-trial nicotine using associative and unrelated word-lists, when volunteers were instructed to use an associative mnemonic strategy. We found no main effect of nicotine, but when volunteers were distracted from rehearsal, related words were recalled better than unrelated words. Experiment 4 was a positive control for the timing of nicotine administration within our experimental design, and this showed that pre-trial nicotine not only improved free recall but differentially enhanced the recall of category words over unrelated words. We conclude that nicotine does modulate memory, that associative aspects of verbal memory in particular are sensitive to modulation by nicotine, and that the effects are more reliably observed with pre-trial than with post-trial administration. The conditions under which post-trial effects can be observed remain unclear.     

Lack of effect of cimetidine on cigarette smoking

Summary The efficacy of cimetidine as a treatment that could reduce smoking in heavily dependent smokers has been determined. In a randomised, double-blind, double-crossover experiment, 43 heavy smokers were divided into two groups, one receiving cimetidine 400 mg orally three times a day, and the other receiving placebo for two weeks followed by the alternative treatment (placebo or cimetidine).No significant difference in the mean alveolar carbon monoxide, nicotine or cotinine levels was found between the two treatment groups compared to baseline. Since the alveolar carbon monoxide level reflects the intensity of smoking behaviour, the results suggest that no change in smoking behaviour occurred in the subjects.Contrary to our previous findings that cimetidine decreased the total body clearance of nicotine by 30% in a population of non-smokers, in the heavily dependent smokers, cimetidine did not appear to alter nicotine elimination. One possible explanation for the discrepancy is that tobacco smoking is known to induce nicotine metabolism and the induction might have offset any effect of cimetidine on nicotine elimination.Cimetidine does not appear to be a useful treatment leading to a reduction or cessation of cigarette smoking.     

Meta-analysis of studies investigating one-year effectiveness of transdermal nicotine patches for smoking cessation.

PURPOSE: The one-year effectiveness of transdermal nicotine patches versus placebo patches for smoking cessation based on continuous or sustained abstinence was studied. METHODS: A literature search of MEDLINE (PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials up to April 2006 was conducted. Articles containing relevant keywords were reviewed by two evaluators independently. To be considered for inclusion in the meta-analysis, studies had to be randomized clinical trials with a transdermal nicotine patch group and a placebo patch group, had to include at least one year of follow-up, had to have abstinence biochemically verified, and had to include the odds ratio (OR) as an outcome measure. RESULTS: Sixteen trials met the selection criteria. The total number of subjects was 9457 (6084 in the nicotine patch group and 3373 in the placebo patch group). The pooled OR for smoking abstinence at one year for the nicotine patch group versus the placebo patch group was 1.79 (95% confidence interval [CI], 1.55-2.08). The pooled OR for one-year continuous or sustained abstinence for the nicotine patch compared with placebo, excluding four studies reporting only point-prevalence abstinence, was 1.75 (95% CI, 1.49-2.05). CONCLUSION: A meta-analysis of trials of transdermal nicotine patch therapy versus placebo for smoking cessation yielded ORs for smoking abstinence of about 1.8 at one year after the start of therapy. ORs were similar whether the endpoint was point-prevalence abstinence, continuous or sustained abstinence, or both.     

Personality related effects of nicotine, mode of application, and expectancies on performance, emotional states, and desire for smoking

 Three separate factors relevant to nicotine effects have been investigated in this experiment in combination: the experimentally induced expectation about receiving a sham or a nicotine cigarette, the mode of application of nicotine by a tablet, by a cigarette or not at all, while the belief of receiving the nicotine via smoking was held constant in each condition (by nicotine or sham smoking), and the personality factors of extraversion or neuroticism, respectively. Ninety-six healthy female student smokers were tested in a 2 × 3 × 2 factorial group comparison design with respect to critical flicker fusion and reaction time performance as well as to self-ratings on emotional and cortical arousal and ratings on desire for further cigarettes (satisfaction from smoking a single cigarette containing either 0.8 mg nicotine or a sham cigarette). In each case, a tablet containing either nicotine or placebo was administered together with the cigarette. The results showed that performance is sensitive to interaction effects of instruction and mode of application. The instruction of sham or nicotine assignment when applied with a congruent treatment (sham with a sham cigarette, or nicotine with a nicotine cigarette) both increased performance, while groups with discordant information showed worse performance. The administration of nicotine by tablets or by smoking differs considerably, nicotine cigarettes causing a stronger increase in emotional arousal, tablets rather a decrease or no effect, while the true placebo condition increases arousal due to deprivation effects. This leads to an enhancement of the nicotine effect with real smoking and to reactive increase of effort when sham smoking. The instruction affects alertness, the nicotine illusion leading to a lower reduction in subjective reports of alertness and concentration than that observed with the sham instruction. Neurotic subjects become more anxious and tense with nicotine cigarettes than stable subjects. This effect is less pronounced or even reversed with tablets. No interactions with instructions are observed with neuroticism. Extraverts tend to show a decrease in performance but an increase in alertness with the instruction of receiving nicotine as opposed to the sham expectation, whereas introverts behave the opposite way. Subjective ratings on arousal seem to follow the law of transmarginal inhibition, with extraverts being pushed from low arousal to high and introverts vice versa by the mere expectation. Received: 11 February 1997/Final version: 30 June 1997     

Mecamylamine blockade of both positive and negative effects of IV nicotine in human volunteers

The ganglionic blocker mecamylamine blocks the positive reinforcing effects of IV nicotine, but has been shown to increase cigarette smoking behavior under some conditions. The effects of mecamylamine on subjective and physiologic responses to IV nicotine were evaluated in seven healthy male volunteer cigarette smokers who provided informed consent and resided on a clinical pharmacology research unit. On four separate days, each subject was given a different oral dose of mecamylamine (placebo, 5, 10, or 20 mg). One hour later subjects received the first of four doses of IV nicotine (placebo, 0.75, 1.5, and 3.0 mg); the remaining injections were given at 1-h intervals. Both the positive effects following 0.75 mg and negative effects following 3.0 mg of nicotine were significantly reversed by mecamylamine. Thus, the mecamylamine-induced increase in smoking may be due both to competitive blockade of nicotinic receptors and nicotine's reversal of aversive effects.     

The influence of nicotine dose and nicotine dose expectancy on the cognitive and subjective effects of cigarette smoking

This study investigated the independent and interactive effects of nicotine dose and nicotine dose expectancy on smoking outcomes using a 2 (given nicotine vs. placebo) × 2 (told nicotine vs. placebo) Balanced Placebo Design (BPD). Smokers (N = 148) completed the Rapid Visual Information Processing Task (RVIP) and measures of smoking urge, mood, and cigarette ratings (e.g., satisfying) after smoking a nicotine or placebo cigarette crossed with instructions that the cigarette contained either nicotine or no nicotine. Nicotine cigarettes (0.6 mg nicotine) produced better sustained attention performance than placebos as indicated by RVIP reaction time, hits, and sensitivity (A'). Nicotine cigarettes also produced better mood and greater rewarding subjective effects of the cigarettes on 11 of 11 dimensions compared to placebos. Nicotine instructions resulted in fewer RVIP false alarms, better mood, and greater rewarding subjective effects of the cigarettes on 9 of 11 dimensions compared to placebo instructions. Nicotine dose by nicotine dose expectancy interactions were also observed for urge and tension-anxiety, such that the dose expectancy manipulation produced differential effects only among those who smoked placebo cigarettes. In contrast a significant interaction for self-reported vigor-activity demonstrated that the dose expectancy manipulation produced effects only among those who smoked nicotine cigarettes. This study provides additional evidence that nicotine improves cognitive performance, and provides initial evidence that denicotinized cigarettes smoked under the guise that they contain nicotine influence cognitive performance, albeit with less robust effects than nicotine. These data may inform the development of expectancy-based interventions for tobacco dependence.     

Effect of transdermal nicotine patches on cigarette smoking: a double blind crossover study

The effect of transdermal nicotine patches on ad libitum cigarette smoking was examined in 30 subjects by measuring behavioural, biochemical and subjective aspects of smoking during a week of smoking without patches, and then a week each of nicotine and placebo patches in a randomised double blind crossover design. While wearing nicotine patches the subjects did not reduce the number of cigarettes smoked, but their expired carbon monoxide was reduced by 14%, they obtained less satisfaction from their cigarettes, and reported fewer and weaker urges to smoke. Down-regulation of nicotine intake from cigarettes was imprecise, such that when subjects wore nicotine patches their post-cigarette plasma nicotine concentration increased to an average of 45 ng/ml compared with 37 ng/ml in both no patch and placebo patch conditions. As the nicotine patches produced a plasma nicotine concentration of 15.9 ng/ml in abstinent subjects, this suggests a 22% reduction in nicotine intake from cigarettes while wearing nicotine patches. No serious symptoms of nicotine overdose were reported. It is suggested that the continuous absorption of nicotine from the patch may cause a build-up of acute tolerance to both toxic and pleasant subjective effects from smoking.     

The influence of alcohol pre-treatment on the discriminative stimulus, subjective, and relative reinforcing effects of nicotine

Alcohol intake may acutely alter the discriminative stimulus and subjective effects of nicotine, perhaps explaining why alcohol increases tobacco smoking. In this study, cigarette smokers were initially trained to discriminate 20 microg/kg nicotine by nasal spray from placebo. Three sessions then followed, in which the generalization of nicotine discrimination was tested across a range of doses (0--20 microg/kg) following pre-treatment with 0, 0.4, and 0.8 g/kg alcohol p.o. Intermittent 'topping' doses of alcohol maintained a steady breath alcohol level (BAL) throughout testing. Generalization testing involved both two- and three-choice ('novel' option) procedures. A visual discrimination task was also conducted to determine the specificity of effects of alcohol. Subjective and cardiovascular measures were obtained concurrent with discrimination responding. The relative reinforcing effects of nicotine were assessed after the end of generalization testing using a choice procedure. Alcohol pre-treatment had no significant effects on nicotine discrimination or self-administration behavior. Alcohol and nicotine each influenced selected subjective responses and heart rate, but virtually no interactions between the drugs were observed. Within the limitations of this study, these results do not support the notion that alcohol acutely alters nicotine's discriminative stimulus, subjective, or relative reinforcing effects at these low nicotine doses. Acute effects of alcohol on smoking behavior may be due to alterations in other effects of nicotine intake or in non-nicotine effects of tobacco smoking.     

Attention,memory, and cigarette smoking

Four experiments tested the effects of smoking one cigarette on verbal memory and attention. In Experiment I, 18 men were tested under three conditions in a repeated-measures design (pretrial smoking, posttrial smoking, no smoking). Recall of a 50-word list was tested immediately and after intervals of 10 and 45 min. Pretrial smoking resulted in improved recall 10 and 45 min after learing, but not immediately. Posttrial smoking was ineffectual. In Experiment II, three posttrial smoking intervals (1, 5, and 30 min after presentation of a 20-word list) were compared with pretrial smoking and no smoking using a between-subjects design. The 76 light, moderate, and heavy smokers in Experiment II smoked a 1.38 mg nicotine cigarette and were tested 24 h later. Improved recall occurred for pretrial smoking, but not for any posttrial smoking interval and for light and moderate smokers only. Experiment III compared a low (0.40 mg) and high (1.38 mg) level of nicotine cigarette in light and heavy smokers using pretrial smoking. The high-nicotine cigarette resulted in improved recall for both immediate- and delayed-recall tests. The lownicotine cigarette was less effective. Light and heavy smokers different in effect of smoking on heart rate, but not in effect of smoking on recall. Experiment IV found no effect of smoking on depth of processing. The possible mechanisms by which nicotine affects recall are discussed.     

Effect of nicotine on ATPase, catalase and calcium levels in the presence of oligoelements in brain regions of young rats

The effect of nicotine on membrane alterations and fluidity changes in very young models remains unclear. The aim of this study was to evaluate the effect of nicotine on total ATPase, H(2)O(2) and calcium in brain of young rats in the presence of oligoelements. Male Wistar rats (weight 80 g) received intraperitoneally either a single dose or repeated doses for 4 days as follows: Group 1 (control) NaCl 0.9%; group 2 nicotine (1mg/kg); group 3 oligoelements (50 μl); and group 4 nicotine (1mg/kg) + oligoelements (50 μl). The brain regions (cortex, hemispheres and cerebellum + medulla oblongata) of each rat were then obtained to measure the concentrations of total ATPase, H(2)O(2) and calcium using spectrophotometric methods. RESULTS: Total ATPase increased significantly (p < 0.05) in groups treated with oligoelements in repeated doses in hemisphere region, and in groups that received oligoelements + nicotine in single or repeated doses in medulla oblongata. Catalase showed significant decreased in cerebellum/medulla oblongata. Results suggest that nicotine induces changes in membrane fluidity in brain of young rats, and that ATPase could be a biomarker of nicotine consumption in young subjects.     

Nicotine gum in smoking cessation: a placebo-controlled, double-blind trial

Sixty subjects were run in a study comparing the use of nicotine gum with placebo gum during cessation from smoking. Subjects were given clinic support and chewed the gum ad libitum. A survival analysis showed the two groups differed significantly in successful abstinence over time (p less than .03). Differences between groups appeared early (within weeks) and, at six months, a 28% superiority of nicotine over placebo gum was demonstrated with mean success rates of 48% and 20%, respectively. Between six months and one year, relapse in the nicotine group accounted for the 30% vs. 20% success rates for nicotine and placebo observed at one year. In a pilot study ("dispensary") testing the efficacy of the two gums when intervention was minimal, subjects in both groups resumed smoking within the first two weeks. The enhanced short-term success rates with nicotine gum in the clinic study are attributed to an effective interaction between use of the active preparation and clinic support. Long-term cessation may require extended maintenance procedures and/or an identification of optimal gum use.     

Transdermal nicotine for smoking cessation in postmenopausal women

This study examined the efficacy of transdermal nicotine in postmenopausal smokers, and whether a history of depression or hormone replacement therapy (HRT) moderated smoking cessation outcomes. Postmenopausal smokers (N=152) received intensive smoking cessation counseling and were randomly assigned to use either a 21-mg nicotine patch for 3 months, with a 1-month taper, or a placebo patch. The primary outcome was biochemically validated 7-day point prevalence smoking abstinence during treatment (i.e., 1, 2, 6, and 12 weeks after the quit date) and 1 year after study medication was discontinued. Subjects who received transdermal nicotine were significantly more likely than placebo-treated subjects to remain abstinent from smoking during treatment, but not at the 1-year follow-up. The majority of subjects (>50%) in both groups accurately identified their treatment assignment. History of depression was associated with a decreased likelihood to abstain from smoking throughout the study. HRT did not moderate smoking outcomes. These data indicate that transdermal nicotine may provide short-term benefits for smoking cessation in postmenopausal women. However, efforts are needed to improve long-term abstinence rates and smoking outcomes among women with a history of depression.     

Postintervention effect of nicotine replacement therapy on smoking reduction in smokers who are unwilling to quit: randomized trial

The objective of this study was to assess the post-intervention effect of nicotine replacement therapy on reduction of cigarette consumption 1.5 years after the end of a 6-month treatment. Heavy smokers who had no intention of quitting smoking were recruited from the general population and were randomly assigned to a treatment of nicotine (choice of a 15-mg nicotine patch, a 4-mg nicotine gum, and/or a 10-mg nicotine inhaler, n = 265), matching placebo products (n = 269), or no intervention (n = 389). Products were sent to participants by mail. Education was limited to a booklet. Of 923 participants, 879 (95%) were followed 6 months after randomization and 846 (92%) were followed after 26 months. Mean baseline consumption was 30 cigarettes/day in all groups. After 6 months, cigarette consumption had decreased by a mean of 10.9 cigarettes/day in the nicotine group, 8.7 in the placebo group, and 4.9 among controls (P < or = 0.02 for all pairwise comparisons). After 26 months, compared with baseline, cigarette consumption had decreased by a mean of 9.8 cigarettes/day in the nicotine group, 7.7 in the placebo group, and 7.7 among controls (nicotine vs. placebo or control: P < or = 0.03). After 2 years, smoking cessation rates did not differ significantly among groups (nicotine 11.7%, placebo 9.3%, control, 10.0%; P = 0.6). Thus, a slight effect of nicotine replacement therapy on reduction of cigarette consumption was maintained 1.5 years after the end of the 6-month treatment, but the initially observed placebo effect was not maintained. Nicotine replacement therapy for smoking reduction had no deleterious impact on smoking cessation.