Nicotine and cotinine replacement when nicotine nasal spray is used to quit smoking

Nicotine nasal spray (NNS) is generally considered to be an effective smoking cessation aid, but all studies to date of NNS effectiveness have also utilized group therapy sessions or frequent laboratory visits to support their subjects’ stop smoking efforts. We studied 50 volunteers before they attempted to quit smoking and again at 1, 2 and 3 months after they received NNS to assist them in quitting smoking. No other stop smoking intervention was used, which more closely mimics the common practice of many individuals trying to stop smoking with the aid of a nicotine replacement product but without other supportive interventions. We found that 50% of the subjects quit smoking for the first month, 34% were still abstinent after 2 months and 32% quit smoking for 3 months. Those who quit smoking for the entire 3 months and who continued regular NNS use throughout had 67% cotinine replacement at the end of the first month, while another group which quit smoking for only the first month with the aid of NNS had 42% cotinine replacement at the end of that month. Our data confirm that NNS is an effective smoking cessation aid, but our abstinent rate at 3 months is slightly lower than in other studies in which group therapy was provided. Our data also indicate that higher NNS-induced cotinine replacement during the first month of quitting smoking (suggesting more frequent use of NNS) is associated with longer term quit-smoking success rate. Received: 4 June 1997/Final version: 19 December 1997     

Good relationship between saliva cotinine kinetics and plasma cotinine kinetics after smoking one cigarette

This study investigated the relationship between plasma and saliva cotinine kinetics after smoking one cigarette and the relationship between cotinine kinetics and estimated nicotine intake, which was calculated as mouth level exposure (MLE) of nicotine, from smoking two test cigarettes with different nicotine yields. This study was conducted in 16 healthy adult Japanese smokers, who did not have null nor reduced-activity alleles of CYP2A6, with a quasi-randomized crossover design of smoking a low-tar cigarette or a high-tar cigarette. Saliva cotinine showed similar concentration profiles to plasma cotinine, and all of the calculated pharmacokinetic parameters of cotinine showed the same values in plasma and saliva. The C_max and AUC of cotinine showed almost the same dose-responsiveness to the estimated MLE of nicotine between plasma and saliva, but the t_max and t_1/2 of cotinine were not affected by the estimated MLE of nicotine in either plasma or saliva. The results show that saliva cotinine kinetics reflects plasma cotinine kinetics, and measurement of saliva cotinine concentration gives the same information as plasma cotinine on the nicotine intake. Thus, saliva cotinine would be a good and less-invasive exposure marker of cigarette smoke, reflecting the plasma cotinine concentration and kinetics.     

Effects of cotinine on cigarette self-administration

Previous studies have shown that cotinine, a metabolite of nicotine, antagonizes some of the effects of nicotine. One study showed that cotinine eliminates the beneficial effects of the nicotine patch in reducing cigarette withdrawal symptoms. The purpose of this study was to examine the effects of various doses of cotinine on cigarette self-administration. Subjects were randomly assigned to one of three doses of cotinine fumarate (40, 80 and 160 mg) and placebo, each for a period of 10 days, in a randomized order. Outcome variables included measures of nicotine intake and subjective responses to smoked cigarettes. Results showed no differences in the number of cigarettes smoked, carbon monoxide levels, and weights of cigarette butts across the various doses of cotinine and placebo. However, higher nicotine serum levels were observed in the 160 mg cotinine fumarate condition compared to placebo and to 40 mg cotinine fumarate. No systematic effects of cotinine on subjective responses to cigarettes were observed. Cotinine appears potentially to have a selective modulatory effect on nicotine withdrawal symptoms but not on cigarette smoking. Received: 2 September 1997 / Final version: 30 December 1997     

Transdermal nicotine in smoking cessation

Summary A systematic search of the literature was made to identify relevant reports of clinical trials of transdermal nicotine, followed by detailed statistical analysis of the results to calculate a pooled estimate of the rate of smoking cessation. Both a fixed effect and a random effects model were used to calculate pooled estimates.The pooled odds ratio (OR) for short-term smoking cessation in favour of the transdermal patches was OR=3.10. Using a random effects model, the risk difference (RD) in favour of the transdermal patches was RD=0.25. The corresponding values for long-term cessation were OR=2.26 and RD=0.11. Skin irritation was a common adverse effect with incidence rates ranging up to about 70%.Nicotine transdermal patches were effective in promoting smoking cessation both in the short-term, with assessments at 3 to 10 weeks, and in the long-term, with assessment at 24 to 52 weeks. Long-term abstinence rates in subjects treated with nicotine patches for a few weeks remained higher than in subjects treated with placebo patches. Adverse effects were usually minor and transient, although subjects with a sensitive skin may find the applications intolerable. Further studies are required to confirm the value of nicotine patches in promoting smoking cessation in the absence of professional medical support and in general medical practices in the community.     

Effects of a nicotine-enriched cigarette on nicotine titration,daily cigarette consumption,and levels of carbon monoxide,cotinine, and nicotine

To test whether cigarettes with low tar, low carbon monoxide, and medium nicotine yield produce less dangerous effects than cigarettes low in tar and CO but high in nicotine, 12 subjects were recruited to smoke nicotine-enriched cigarettes. The subjects smoked three types of cigarettes in the three experimental conditions: (1) their own brand; (2) cigarettes with 4.8 mg tar, 4.0mg CO, and 0.5 mg nicotine; (3) cigarettes with 5.8 mg tar, 4.1 mg CO, and 1.1 mg nicotine. Subjects monitored their daily consumption for 12 weeks; 4 weeks for each condition. During laboratory visits, the subjects smoked a cigarette while their heart rate and carbon monoxide in expired air were measured pre- and post-smoking. A blood sample was drawn and analyzed for nicotine and cotinine in each experimental condition. No significant differences in daily cigarette consumption were found, although a trend (P<0.07) in the direction of fewer nicotine-enriched cigarettes per day was found. Levels of CO varied significantly among the three conditions: The subjects' own brands yielded the highest level, while the nicotine-enriched cigarette yielded the lowest level. No differences were found for nicotine or cotinine levels. A second purpose of the experiment was to record the degree of nicotine titration displayed by individual smokers, tar and CO levels remained constant in the experimental cigarettes. No general titration effect was observed, although for daily consumption it approached significance. When the subjects' nicotine dependence, measured with a tolerance questionnaire, was taken into acount, a correlation with daily consumption was found (r=77, P<0.005). A cigarette with low tar and CO, but medium to high nicotine yield, would seem to produce less hazardous effects and is worthy of further investigation. The controversial question of whether smokers titrate for nicotine is a function of the individual's nicotine dependence.     

Quitting cigarette smoking produces minimal loss of chronic tolerance to nicotine

RATIONALE: Long-term exposure to nicotine is associated with chronic tolerance to its acute effects, adaptation that may lead to tobacco dependence. The time course for loss of this tolerance after cessation of exposure is not known in humans but could relate to risk of smoking relapse. OBJECTIVES: We examined changes in responses to nicotine as a function of days, weeks, or years of smoking cessation in formerly dependent smokers to determine at what point sensitivity to nicotine is reinstated (i.e., loss of tolerance). METHODS: Acute subjective, cardiovascular, performance, and reinforcing (self-administration) effects of nicotine nasal spray (0-20 microg/kg) were assessed prospectively in men and women smokers before and then day-by-day (study 1) or 3 weeks (study 2) after stopping smoking. A smoking resumption period (study 1) and a group of non-quitting smokers (study 2) were included to control for the passage of time. These effects were also compared cross-sectionally between those who had quit for 1-4 years and those who had for 6-19 years in a separate sample of long-time ex-smokers to determine whether lengthier abstinence causes greater loss of tolerance (study 3). RESULTS: No clear loss of tolerance was observed on any measure in studies 1 or 2, suggesting that chronic tolerance is fully maintained for at least weeks after quitting smoking. Sensitivity to nicotine's effects was also not different as a function of years quit in study 3. CONCLUSIONS: Chronic tolerance to nicotine is not lost within several weeks of quitting smoking and may not change even after years of abstinence from tobacco use.     

Arterial/venous plasma nicotine concentrations following nicotine nasal spray

Background and objectives: Arterial (A) and venous (V) plasma nicotine and cotinine concentrations were measured after nasal nicotine spray in tobacco smokers of both genders. The hypothesis for this research was that a greater A/V difference in plasma nicotine would be present in males than females because males have greater skeletal muscle mass to bind nicotine. Subjects and methods: Nine male and nine female healthy adult smokers were studied. They all abstained from use of tobacco overnight for 10 h or more prior to the study. Nicotine nasal spray was given in doses of 1–2.5 mg total, with half in each nostril while the subject was supine. Both A and V blood samples were obtained prior to and 3, 6, 10, 15, 20, and 30 min post-nasal nicotine spray. Results and conclusions: Nasal nicotine administration produced greater A than V plasma levels. There were no gender differences in A/V nicotine concentrations, disproving the above hypothesis, suggesting that other physiochemical factors besides skeletal muscle mass must be involved. Heart rate increases correlated well with arterial plasma nicotine levels (r=0.77). Males had less variance than females in the expected increase in arterial plasma nicotine concentrations with increased number of nasal sprays. Although there was considerable overlap, mean A cotinine concentrations were consistently slightly larger than V concentrations. Received: 15 February 1999 / Accepted in revised form: 17 August 1999     

Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats

  Rationale: The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. Objective: The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. Methods: Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015, 0.03 and 0.06 mg/kg per infusion). Results: The two larger unit doses supported reliable self-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50–200 ng/ml) were approximately 2-fold higher than nicotine levels (40–120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. Conclusions: The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence. Received: 14 November 1998 / Final version: 4 January 1999     

Influencing cigarette smoking with nicotine antagonists

Antagonists of nicotine have been used in an attempt to resolve the continuing controversy about the role of nicotine as the primary reinforcer in cigarette smoking. Mecamylamine, an antagonist which readily penetrates to the central nervous system, increased the rate of cigarette smoking by about 30% in laboratory tests; this was accompanied by reduced blood pressure, impaired performance of a digit symbol substitution test, improved hand steadiness, and by dysphoria. The increased smoking may be regarded as self-titration with nicotine, an interpretation which receives some support from results obtained with pentolinium, an antagonist with predominantly peripheral actions. In the doses used, pentolinium did not affect smoking rate, blood pressure, or hand steadiness, but it impaired digit symbol performance and induced dysphoria. The different results with mecamylamine and pentolinium support previous evidence that the action of nicotine in the central nervous system has a small but clearly demonstrable role as a primary reinforcer of the smoking habit.A preliminary account of this work has appeared previously (Jarvik, in press).     

High dose transdermal nicotine therapy for heavy smokers: safety,tolerability and measurement of nicotine and cotinine levels

Transdermal nicotine has been shown to relieve nicotine withdrawal and to double smoking cessation rates compared to placebo in clinical trials. A 21 or 22 mg/day dose provides a steady state serum nicotine that is less than obtained from smoking. Limited information is available about higher nicotine patch doses. To define better the optimal dosing of nicotine patch therapy, we undertook an open-label study to determine the safety and tolerability of 44 mg/day dose for smoking cessation in subjects smoking 20 cigarettes per day. Forty smokers received 44 mg/day of transdermal nicotine for 4 weeks followed by 4 weeks of 22 mg/day. Of the 40 subjects enrolled, 38 (95%) completed the 4 weeks of 44 mg patch therapy and 36 (90%) completed the entire 8 weeks of patch therapy. Non-smokers at week 4 had a mean serum nicotine level of 23.4±11.7 ng/ml and cotinine of 152.2±87.3 ng/ml. Percent replacement was calculated by dividing the steady state level at week 4 by the baseline level while the subjects were smoking their usual number of cigarettes. Percent nicotine replacement for non-smokers at week 4 (while on 44 mg nicotine patch) averaged 158%±108.4, and for cotinine was 112.0±73.8. For nicotine, 33% of non-smokers at week 4 had 100% nicotine replacement and for cotinine 63% 100% replacement. Biochemically confirmed point prevalence smoking cessation rates were 65% and 55% at weeks 4 and 8 of patch therapy, respectively, and self-reported smoking cessation at 3 months was 50%. The most common effect was skin irritation at the patch site. A single subject was admitted for myocardial infarction following step-down from 44 to 22 mg of replacement nicotine. The subject was not smoking and the adverse event was deemed to be not related to the patch therapy. Sleep complaints were reported in 33% of subjects during the 44 mg phase. Other complaints were infrequent. We conclude that 44 mg per 24-h nicotine patch therapy in heavy smokers is safe, tolerable, and without significant adverse events.     

The alternative five-factor model of personality, nicotine dependence and relapse after treatment for smoking cessation

Personality is one of several factors that have been related to the initiation, maintenance and cessation of smoking. This paper aims to analyze the relationship between the alternative five-factor model of personality (AFFM), nicotine dependence (ND), nicotine use (NU) and cessation after twelve months of a cognitive–behavioral therapy combined with medication. In this prospective study, a sample of 103 smokers who were taking part in a workplace smoking cessation intervention, answered the Zuckerman–Kuhlman Personality Questionnaire. ND and NU were measured with the Fagerström Test for the Nicotine Dependence (FTND) and the number of cigarettes smoked per day (CPD), respectively. Tobacco cessation was self-reported at twelve months follow-up and biologically confirmed. Results varied according to gender. In men, low scores on Sociability predicted high ND and large number of CPD. In addition, low scores on Sensation Seeking and high scores on Impulsivity predicted also a high smoking rate at baseline. No personality traits were found to explain ND in women, but high Impulsivity–Sensation Seeking and General Activity predicted high CPD. Predictors of cessation also differed by gender. Apart from FTND level, high levels on Impulsivity predicted relapse in males. In women, high levels on Sociability predicted relapse. This model correctly classified two thirds of abstainers and relapsers for men and three fourths for women at 12 months. Furthermore an interaction between personality and gender was observed. The AFFM appears to have a substantial power for predicting cessation. Personality assessment when beginning treatment for smoking cessation could allow incorporating strategies to improve outcomes.     

Double-blind placebo controlled trial of dextrose tablets and nicotine patch in smoking cessation

 In a placebo-controlled double-blind trial 308 smokers were individually randomly allocated to one of four groups: 1) 3 g dextrose tablets and 15 mg nicotine transdermal patch; 2) dextrose and placebo patch; 3) placebo tablets and nicotine patch; 4) placebo tablets and placebo patch. Patients were scheduled to attend weekly smokers clinic sessions starting 1 week before the quit date and continue for 4 weeks after that date. The primary outcome variable was biochemically verified abstinence at the final session, four weeks after the scheduled quit date. The proportion of smokers abstinent in the four groups was as follows: 49% – dextrose plus active patch; 44% – dextrose plus placebo patch; 36% – placebo tablet plus active patch; 30% – placebo tablet plus placebo patch. The difference between the dextrose and placebo tablets (13%) was statistically significant (P < 0.01, one-tailed); the difference between the active and placebo patches (6%) was not. There was no significant difference between the effect of the dextrose when accompanied by active versus placebo patches. There was no significant effect of dextrose on weight. The results suggest that dextrose supplementation to the diet may be a cheap and simple aid to giving up smoking. Further research is now needed to establish its long-term efficacy. Received: 7 July 1997/Final version: 26 September 1997     

The influence of offering free transdermal nicotine patches on quit rates in a local health department's smoking cessation program

Nicotine replacement therapy (NRT) has added to the menu of options available to assist cigarette smokers in quit attempts, but cost remains a barrier to access. A quasi-experimental study was carried out to compare quit rates and continuous abstinence from smoking before (n=601) and after (n=311) free nicotine patches were offered to smokers who participated in the Washington County (Maryland) Health Department's "Stop Smoking for Life" group behavioral cessation program. After free NRT was offered, the quit rates upon completion of the program increased from 38% to 65% [difference 27%; 95% confidence limits (CL) 21%, 34%]. The difference in continuos abstinence from smoking between the two groups was no longer statistically significant after 6 months of follow-up, reflecting the more rapid rate of reversion to smoking that occurred during the 18-month follow-up period among the free NRT group who had quit [adjusted rate ratio (RR) 1.35; 95% CL 1.03, 1.78]. Enrollment during the first 18 months after free NRT was 37% greater than the program's first 18 months (P=.08). In conclusion, adding free nicotine patches to a smoking cessation program was associated with increased program enrollment and significantly increased short-term-but not long-term-quit rates. The rapid reversion to smoking in the group who received free nicotine patches could potentially be obviated if participants extend their use of nicotine patches after the free 6-week supply is exhausted.     

Association between nicotine replacement therapy use in pregnancy and smoking cessation

Background

There is an urgent need to find better ways of helping pregnant smokers to stop. Randomized controlled trials (RCTs) have not detected an effect of nicotine replacement therapy (NRT) for smoking cessation in pregnancy. This may be because of inadequate dosing because of faster nicotine metabolism in this group. In England, many pregnant smokers use single form and combination NRT (patch plus a faster acting form). This correlational study examined whether the latter is associated with higher quit rates.

Methods

Routinely collected data from 3880 pregnant smokers attempting to stop in one of 44 Stop Smoking Services in England. The outcome measure was 4-week quit rates, verified by expired-air carbon monoxide level < 10 ppm. Outcome was compared between those not using medication versus using single form NRT (patch or one of the faster acting forms), or combination NRT. Potential confounders were intervention setting (specialist clinic, home visit, primary care, other), intervention type (one-to-one, group, drop-in, other), months pregnant, age, ethnicity and occupational group in multi-level logistic regressions.

Results

After adjustment, combination NRT was associated with higher odds of quitting compared with no medication (OR = 1.93, 95% CI = 1.13–3.29, p = 0.016), whereas single NRT showed no benefit (OR = 1.06, 95% CI = 0.60–1.86, p = 0.84).

Conclusions

Use of a combination of nicotine patch and a faster acting form may confer a benefit in terms of promoting smoking cessation during pregnancy. While this conclusion is based on correlational data, it lends support to continuing this treatment option pending confirmation by an RCT.     

Long-term nicotine substitution after application of a 16-hour nicotine patch in smoking cessation

Summary The purpose of the study was to examine long-term nicotine substitution and its variability during use of a nicotine patch. In two smoking cessation studies a 16-h nicotine patch, releasing 15 mg nicotine, was applied daily for 16 h over 12 weeks, to 167 smokers. Salivary cotinine was highly correlated with plasma cotinine (r = 0.93), and the concentration of cotinine in a single sample in the afternoon was well correlated with the AUC_cotinine over 24 h (r = 0.94). The salivary cotinine concentration after 1 week in 60 abstainers was 183 ng · ml^–. After 3, 6 and 12 weeks the cotinine concentrations were 86%, 79% and 59% of the 1-week value. The degree of nicotine compensation attained by the patch after 1 week was 52% (SD 24%) in subjects who succeeded in stopping smoking for at least 3 weeks. A quarter of the subjects achieved a compensation of less than 35% of their usual nicotine intake. Nicotine substitution with this 16-h nicotine patch was stable and the risk of overcompensation was small in this group of smokers.     

A naturalistic cohort study on effectiveness,safety and usage pattern of an over-the-counter nicotine patch. Cohort study on smoking cessation

Introduction Nicotine replacement therapies (NRT) are effective for smoking cessation. After having received over-the-counter (OTC) status in Germany, concerns grew about effectiveness, increased risks, especially of adverse cardiovascular reactions, and inappropriate use of NRT. Thus, a pharmacy-based cohort study was launched.Objectives To assess effectiveness, safety and appropriateness of use of an OTC nicotine patch (Nicotinell, Novartis Ltd.). Every customer who bought an OTC Nicotinell patch was eligible. All data were collected by self-administered questionnaires at weeks 2, 4, 8, 12 and 24 after inclusion. Six hundred and thirty-three customers were admitted, median duration of smoking was 19 years. Of the participants, 6% smoked up to 10 cigarettes per day, 43.6% between 11 and 20, 34.3% between 21 and 30, and 16.1% more than 30 cigarettes. Twenty-four weeks later, 351 participants replied: 28% (177 of 633) had quit smoking completely. Considering replies only the proportion of complete responders raised to 50.4%. There were no serious adverse events reported; 62.9% complied with the directions for use and did not use the patch for more than 3 months. About 45% smoked simultaneously with NRT. Pharmacy-based cohort studies are feasible. This study indicates that the nicotine patch is effective and safe in an OTC setting. There is still room to improve compliance with the directions for use.     

Can cigarette size and nicotine content influence smoking and puffing rates?

The stimuli controlling the rate at which people smoke cigarettes have not been clearly defined. On the hypothesis that smoking is basically nicotine-seeking behavior. nicotine available to the subject was experimentally manipulated through controlling cigarette size and nicotine content. In Experiment I, subjects given their own cigarettes in whole, half, quarter, and eighth lengths, increased the number of cigarettes smoked and number of puffs to compensate for reductions in size. Satisfaction was directly related to cigarette length. In Experiment II, subjects given special cigarettes delivering 0.2 or 2.0 mg nicotine/cigarette smoked significantly more of the low than of the high nicotine cigarettes and took significantly more puffs. As in Experiment I, significantly more quarter length than full length cigarettes were smoked, but total number of puffs did not differe. These results support the hypothesis that nicotine controls smoking behavior.     

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.     

Intra- and inter-individual variability in urinary nicotine excretion and plasma cotinine in adult cigarette smokers

Urinary nicotine equivalents (NE) and plasma cotinine are widely used as a biomarker for exposure to tobacco products, but there is limited information on intra- and inter-individual variability in the literature. Data were gathered from 13 randomized controlled clinical studies sponsored by Philip Morris USA, with study durations between 2 and 8 days for the short term (ST) and 3–12 months for the long term (LT) studies. Coefficients of variation (CV) were compared and a linear mixed model was used to partition the total study variability into inter- and intra-individual variability. In the ST and LT studies respectively, the root–mean–square (RMS) intra-individual CV was 19% and 29% for NE (mg/24 h); 19% and 33% for NE (mg/cig) and 13% and 22% for plasma cotinine. The RSM inter-individual CV was 38% and 38% for NE (mg/24 h), 25% and 32% for NE (mg/cig) and 38% and 37% for plasma cotinine, in ST and LT study, respectively. Intra-individual CV was smaller in ST studies than in LT studies, and was significantly less than inter-individual CV in ST studies. Daily cigarette consumption alone could not explain all the variability in NE and plasma cotinine. The variability estimates could be used for clinical study design of clinical and developing regulatory guidance.     

Effect of instructions and nicotine on smoking cessation,withdrawal symptoms and self-administration of nicotine gum

Seventy-seven smokers quit smoking and were randomly assigned to a 3×2 design contrasting instructions (told received nicotine gum versus told received placebo gum versus not told which gum received) and receipt of nicotine (received nicotine gum versus received placebo gum). Both being told one received nicotine and actual recept of nicotine increased the number of days abstinent and decreased the number of cigarettes smoked (P<0.05). Receipt of nicotine but not instructions appeared to influence withdrawal (P=0.06). Instructions but not recept of nicotine appeared to influence craving (P=0.08), gum selfadministration (P=0.06) and reported helpfulness of the gum (P=0.02). Neither nicotine nor instructions influenced side-effects. Instructions and nicotine interacted in several ways. For example, nicotine appeared to increase abstinence in the blind and told placebo conditions more than in the told nicotine condition (P<0.05). Our results suggest the effects of instructions and nicotine 1) are not mutually exclusive, 2) vary across dependent variables and 3) can interact such that instructions modify the therapeutic and subjective effects of nicotine.