Acute doses of d-amphetamine and bupropion increase cigarette smoking

RATIONALE: Bupropion is used clinically as a treatment for smoking cessation, but the processes by which it reduces smoking are poorly understood. Bupropion shares some neurochemical actions and behavioral effects with the psychostimulant amphetamine, and it has been shown that amphetamine increases smoking when administered acutely. The effects of single doses of bupropion on smoking have not been studied but, based on its similarities to amphetamine, we postulated that acute bupropion would also increase smoking. OBJECTIVE: To measure the effects of single doses of amphetamine and bupropion on smoking and craving for cigarettes in smokers. METHODS: Cigarette smokers who were not trying to quit participated in a three-session study in which they received placebo and a single dose of either d-amphetamine sulfate (10 and 20 mg; n=10) or bupropion hydrochloride (150 and 300 mg; n=12) after overnight abstinence. The three outcome measures were: i) subjective and behavioral effects of amphetamine and bupropion after a period of acute abstinence, ii) effects of amphetamine and bupropion on subjective responses to a single, smoked cigarette, and iii) effects of the drugs on number of cigarettes smoked during an ad libitum smoking period. RESULTS: After the acute abstinence and before smoking, both amphetamine and bupropion increased self-reported mood and euphoria, but did not change ratings of craving or withdrawal. After subjects smoked a single smoked cigarette, they reported that bupropion reduced ratings of "buzzed" and "intensity". During the period of ad libitum smoking both amphetamine and bupropion increased the number of cigarettes smoked. CONCLUSION: Acute doses of both bupropion and amphetamine increase smoking in non-treatment-seeking smokers without altering ratings of craving or withdrawal. Bupropion reduced some of the sensory responses to the smoked cigarette. It remains to be determined why bupropion increases smoking when administered acutely under controlled conditions, while it helps to reduce smoking in patients trying to quit.     

Reaction time performance as a function of cigarette smoking procedure

Laboratory studies examining the effects of cigarette smoking on behavior have routinely employed a variety of standardized smoking procedures. This study examined whether reaction time performance after smoking varied as a function of the cigarette smoking procedure employed. Twelve regular smokers were tested on a reaction time task after smoking on three different occasions. In each session, they smoked by one of the three following procedures: (1) ad libitum smoking of their own cigarette; (2) ad libitum smoking of a standard cigarette; (3) smoking a standard cigarette with a prescribed puff pattern. The results show that reaction time performance was significantly faster after smoking under the latter two conditions relative to the subjects' performance after ad libitum smoking of their own cigarette. These findings illustrate that experimental requirements which are commonly imposed upon subjects may affect the results obtained.     

Haloperidol reduces smoking of both nicotine-containing and denicotinized cigarettes

RATIONALE: Studies with laboratory animals and humans suggest that dopamine may play a role in maintaining cigarette smoking behavior via its interactions with nicotine. OBJECTIVES: This study was designed to replicate and extend previous findings showing that the dopamine D2 antagonist, haloperidol, produces blockade of smoking reward and compensatory increases in smoking. METHODS: We studied 20 subjects in a 2x3 within-subjects design, with nicotine-containing or denicotinized cigarettes crossed with oral placebo, haloperidol 1 mg, or haloperidol 2 mg. Subjects attended six sessions during which they received one of the cigarette/drug combinations, and smoked under both controlled and ad libitum conditions. Cigarette and mood ratings and smoking behavior were assessed. RESULTS: Haloperidol reduced the number of cigarettes smoked and the carbon monoxide boost associated with both types of cigarettes, at doses that did not appear to produce clinically significant behavioral effects. CONCLUSIONS: Dopamine appears to play a role in mediating smoking behavior, but this may occur through a non-nicotine mechanism.     

Naltrexone,smoking behaviour and cigarette withdrawal

In order to examine the role of endogenous opioids in the reinforcing effects of nicotine, a double-blind, placebo-controlled, cross-over design was used to study the effects of the opiate antagonist, naltrexone, on smoking behaviour and cigarette withdrawal in 12 heavy smokers. Although naltrexone (50 mg) appeared to reduce the perceived difficulty of abstaining during 24-h cigarette withdrawal, other withdrawal symptoms were unaffected. Naltrexone also had no effect on a variety of biochemical and behavioural measures of nicotine intake or on subjective satisfaction and enjoyment from the first cigarette smoked after 24-h abstinence. Similarly naltrexone (100 mg) had no effect on smoking behaviour, nicotine intake or satisfaction from smoking during a 48-h period of ad libitum smoking. However, during the ad libitum smoking period naltrexone caused mood changes of the kind that occur during tobacco withdrawal. Since nicotine intake and smoking behaviour were unaffected, the mood changes are unlikely to have been mediated by blockade or any other form of opioid interaction with nicotinic mechanisms. These findings provide evidence against the notion that the endogenous opioids are involved in mediating the reinforcing properties of nicotine in smokers under normal conditions.     

Naltrexone reduces the relative reinforcing value of nicotine in a cigarette smoking choice paradigm

Rationale Human behavioral pharmacology studies can examine how medications that target different neurotransmitter systems influence different aspects of smoking. Naltrexone and bupropion have been shown to alter ad lib smoking behavior; however, medication effects on nicotine reward in a cigarette choice paradigm have yet to be investigated.Objective This study explored the effects of an acute dose of naltrexone, bupropion, or placebo on the relative reinforcing value of nicotine from cigarette smoking using new nicotine and de-nicotinized (Quest, 0.6 and 0.05 mg = denicotinized) cigarettes.Methods In a double-blind, within-subjects design, 26 dependent smokers participated in three experimental cigarette smoking sessions following pretreatment with either naltrexone (50 mg), bupropion (300 mg), or placebo. After medication administration and 2 h of monitored deprivation from cigarettes and food, participants rated their responses to the initial exposure to the cigarettes and then participated in four choice sessions over a 2-h period during which they could take four puffs from either cigarette.Results The relative reinforcing value of nicotine, as measured by the number of nicotine puffs chosen out of 16, was significantly lower following naltrexone compared to placebo. There were no effects of an acute dose of bupropion on nicotine choices.Conclusions These results suggest that naltrexone may reduce the relative reinforcing effects of nicotine via cigarette smoking and support ongoing investigation of opioid antagonists as potential smoking cessation pharmacotherapies.     

Methylphenidate increases cigarette smoking

Rationale Methylphenidate (Ritalin) and d-amphetamine (Dexedrine), stimulants commonly prescribed for behavioral problems associated with atttention deficit hyperactivity disorder (ADHD), produce a similar constellation of behavioral effects. The results of previous studies suggest that d-amphetamine increases rates of smoking and the reinforcing effects of smoking. The effects of methylphenidate on smoking have not been assessed although it is the most commonly prescribed pharmacotherapy for ADHD and individuals with ADHD are at increased risk for smoking. Objective In this experiment the acute effects of a range of doses of methylphenidate (5, 10, 20, and 40 mg) and placebo were assessed in ten cigarette smokers who were not attempting to quit and were without ADHD or other Axis I psychiatric disorders. Methods Each dose of methylphenidate was tested once, whereas placebo was tested twice. One hour after ingesting drug, participants were allowed to smoke ad libitum for 4 h. Measures of smoking included total cigarettes smoked, total puffs, latency to the first cigarette, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum, and caloric intake during the 4-h smoking session was calculated. Results Methylphenidate dose dependently increased the total number of cigarettes smoked, number of puffs, and carbon monoxide levels. As expected, methylphenidate dose dependently decreased the number of food items consumed and caloric intake. Conclusions The results of this experiment suggest that methylphenidate, like d-amphetamine, increases rates of cigarette smoking.     

Effects of alcohol pretreatment on human marijuana self-administration

Alcohol and marijuana are frequently used together, yet there has been little study of how the presence of one drug might affect consumption of the other. The present study examined the effects of alcohol pretreatments on marijuana self-administration in a group of 15 males and 5 females who were users of both drugs. During evening sessions in a recreational setting, pairs of subjects consumed drinks containing 0.0, 0.3 or 0.6 g/kg alcohol 30 min before a 60-min period of ad libitum marijuana smoking. Marijuana self-administration was assessed in several ways: by measuring the number of cigarettes smoked, the increase in expired air carbon monoxide resulting from marijuana smoke inhalation, and the increase in heart rate due to THC absorption. None of these variables was significantly affected by the alcohol pretreatments, although substantial individual differences were observed. These results indicate that low to moderate doses of alcohol do not systematically influence marijuana self-administration.     

Effects of marijuana smoking on subjective ratings and tobacco smoking

Multiple measures of tobacco cigarette smoking and subjective and physiological effect were collected during 90 minute test sessions in volunteer cigarette smokers who also had histories of recreational marijuana use. Before sessions, subjects smoked one marijuana cigarette (placebo or 1.29%, 2.84%, 4.00%) using a standardized puffing procedure. Each dose and placebo was given four times to each subject in a randomized block sequence. Marijuana smoking produced dose-related increases in heart rate, ratings of dose strength and drug liking. However, marijuana produced no significant alterations in tobacco cigarette smoking. Puff duration within each marijuana cigarette varied in a fashion similar to that observed in previous studies of tobacco cigarette smoking: puff duration progressively decreased as the cigarette was smoked. This effect is probably due to progressive decreases in resistance to draw as the cigarette is smoked. Expired air carbon monoxide (CO) levels following marijuana smoking were inversely related to marijuana dose, suggesting the occurrence of some compensatory changes in marijuana smoking in response to dose manipulations. It is concluded that, although marijuana produces dose-related effects on physiological and subjective effects and on marijuana smoking behavior, marijuana differs from a variety of other psychoactive drugs previously studied in this paradigm in that no reliable changes in tobacco smoking were produced.     

U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking

Rationale: The role of endogenous opiate systems in cigarette smoking remains unclear. In laboratory animals, opiate antagonists block many of the effects of nicotine, but in humans they do not consistently alter smoking behavior. Objective: This study explored the effects of naltrexone, alone and in combination with nicotine, on smoking behavior. Methods: In a double-blind, double-dummy, within-subjects design, 19 regular smokers received four treatments of 1 week duration: naltrexone tablet (50 mg) plus placebo skin patch, placebo tablet plus nicotine skin patch (21 mg/24 h), naltrexone tablet plus nicotine skin patch, and placebo tablet plus placebo skin patch. During each treatment, subjects rated their responses to nicotine-containing and denicotinized cigarettes in the laboratory, and to their own brand of cigarette smoked ad libitum outside the laboratory. Results: Pretreatment with the nicotine patch attenuated smoking-induced decreases in craving, negative affect, and rates of ad lib smoking, and potentiated the aversiveness of a cigarette. Naltrexone reversed these effects of the nicotine patch, and produced negative effects on mood. Conclusions: The blockade of nicotine’s effects by naltrexone supports a role for opioid mechanisms in cigarette smoking. Received: 9 October 1997/Final version: 3 December 1998     

Smoking topography and nicotine blood levels

Frequency and durational components of smoking topography were measured by a portable smoking device while 10 subjects smoked four cigarettes ad libitum in a non-laboratory environment. Nicotine blood levels were measured before and after smoking each cigarette and serial blood samples for determining nicotine metabolic half-life were obtained the following day. Results showed that change in pre- and post-cigarette nicotine levels and metabolic half-life for nicotine were not related to within-cigarette topography measures or nicotine yield of cigarette, but were significantly related to intercigarette interval.     

Pharmacologic and sensorimotor components of satiation in cigarette smoking

To examine mechanisms underlying satiation in cigarette smoking, 18 smokers received intravenous (i.v.) nicotine, alone or in combination with denicotinized cigarette smoke. Nicotine was administered using programmed presentations of either pulsed injections or continuous infusions, with i.v. saline serving as a control. A high-nicotine cigarette smoke condition (usual brand) was also presented. During each of the six test sessions, subjects were allowed to puff on their usual brands of cigarette ad libitum while the programmed satiation conditions were in force. Administration of i.v. nicotine caused a small suppression of ad libitum smoking behavior; denicotinized smoke produced a significantly larger reduction, showing that short-term satiation is more dependent on the presentation of smoke than delivery of nicotine per se. However, denicotinized smoke alone did not have as much effect as puffs from the usual brands of cigarettes. The combination of i.v. nicotine and denicotinized smoke puffs produced equivalent satiation to that of the usual brand. Cigarette craving and negative affect were partially relieved by iv nicotine presentations as well as by denicotinized smoke, and again the combination of i.v. nicotine and denicotinized smoke approximated the effects of the usual brand. The results of this study underscore the importance of both sensorimotor aspects of smoking and the pharmacologic effects of nicotine in tobacco dependence.     

A pharmacological analysis of stimulant-induced increases in smoking

Rationale Stimulants increase tobacco smoking in healthy adults under controlled laboratory conditions. The mechanisms that mediate stimulant-induced increases in smoking are not known. Objective The purpose of the present experiment was to characterize the pharmacological specificity of stimulant-induced increases in smoking. We tested the effects of methylphenidate and atomoxetine on smoking behavior. Atomoxetine is a norepinephrine transport inhibitor that does not increase dopamine levels in the nucleus accumbens or striatum. If stimulant-induced increases in smoking result from an additive or synergistic effect of these drugs and nicotine on dopamine levels in the nucleus accumbens or striatum, methylphenidate but not atomoxetine should increase smoking. Materials and methods Doses of methylphenidate (10, 20, and 40 mg) and atomoxetine (20, 40, and 80 mg) were tested once while placebo was tested twice in 12 cigarette smokers. One hour after ingesting drug, participants smoked ad libitum for 4 h. Measures of smoking included total cigarettes, total puffs, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum, and food intake was calculated. Results Methylphenidate but not atomoxetine dose-dependently increased the number of cigarettes, puffs, and carbon monoxide levels. Methylphenidate and atomoxetine decreased food intake. Conclusions The results of this experiment are consistent with the notion that stimulant-induced increases in smoking may result from an additive or synergistic effect of these drugs and nicotine on dopamine levels in the nucleus accumbens or striatum. Additional research is needed to more fully understand the pharmacological mechanisms that mediate the relationship between stimulant use and smoking.     

Effects of ventilated cigarette holders on cigarette smoking by humans

Heavy cigarette smokers individually attended daily 3-h test sessions which were run in specially designed cigarette smoking evaluation rooms. Subjects were required to use the cigarette holder provided, and were required to extinguish each cigarette 4 min after the first puff on the cigarette. Other than these restrictions, subjects were allowed to smoke ad libitum. The concentration of delivered tobacco product was varied from 100 to 10% across sessions by using graded commercially available ventilated cigarette holders. As concentration of tobacco product was decreased, rate of puffing and total number of puffs showed robust compensatory increases. Number of cigarettes increased only moderately in response to decreases in tobacco product concentration. There was little change in subjective ratings of strength on smoking satisfaction. Finally, expired air carbon monoxide (CO) values and cigarette butt weights were relatively stable across the four ventilation conditions. These later findings suggest that a significant degree of compensation had occurred in response to the concentration manipulations.     

Effects of single doses of alcohol and caffeine on cigarette smoke puffing behavior

Puffing behavior (number of puffs, puff duration, puff volume, peak pressure, peak flow, peak latency, and puff interval) and pre- to postsmoking delta tidal CO difference were measured in female subjects in order to assess separate and combined effects of ethanol and caffeine. The subjects smoked two cigarettes of their habitual brand in a preliminary familiarizing session and in each of the subsequent four test sessions. The treatments administered after smoking the first cigarette in the test sessions were: alcohol placebo and caffeine placebo; alcohol placebo and caffeine; alcohol and caffeine placebo; alcohol and caffeine. Test-retest reliability across the first cigarette of each session (which was not smoked under the influence of the treatments) was remarkably high for all the puffing parameters. Ethanol in the dose of 0.7 g/kg intensified cigarette smoking of the second cigarette by increasing delta tidal CO, average puff volume, and total puff volume per cigarette, whereas 0.5 g/kg ethanol and 5 mg/kg caffeine given alone or combined with ethanol failed to influence puffing behavior consistently.     

Delay discounting and the behavioural economics of cigarette purchases in smokers: the effects of nicotine deprivation

RATIONALE: In smokers, nicotine deprivation may increase impulsive decision-making and the demand for cigarettes. OBJECTIVES: To investigate the effects of acute nicotine deprivation on (a) the delay discounting of monetary and cigarette rewards, and (b) the behavioural economics of hypothetical cigarette purchases. MATERIALS AND METHODS: A repeated measures design was employed, with participants (daily cigarette smokers, N=30) repeating experimental tasks in two different sessions, once after at least 13 h of abstinence from smoking and once after ad lib smoking. Participants completed measures of cigarette craving, impulsivity, delay discounting and a behavioural economic simulation in which participants made hypothetical purchases of cigarettes and other commodities as the price of cigarettes was systematically varied. RESULTS: Participants showed more pronounced delay discounting of both cigarette and monetary rewards after abstinence compared to after ad lib smoking. In the behavioural economic simulation, nicotine deprivation had no influence on hypothetical cigarette purchases. However, spending on some commodities (alcohol, clothing, household goods, leisure activities and long-distance travel) was reduced as the price of cigarettes increased in order to fund increased spending on cigarettes, although the number of packs of cigarettes purchased actually decreased. CONCLUSIONS: Nicotine deprivation increases impulsive choices for both cigarette and monetary rewards in a delay-discounting task. Results from a behavioural economic simulation suggest that increases in the price of cigarettes may increase smokers' spending on cigarettes, while also reducing the number of cigarettes purchased.     

Smoking topography and carbon monoxide levels in smokers

Factors which effect the expired air carbon monoxide (CO) levels of smokers were examined in matched subject pairs who smoked an equal number of daytime cigarettes but had different CO levels (mean difference = 15.4 ppm). Measures of puff number, duration, and spacing, as well as the amount of CO increase per cigarette (CO boost), were assessed while subjects smoked a single cigarette in daily laboratory sessions. Subjects with relatively high CO levels had larger increases in CO after smoking a single cigarette than did individuals with low CO levels (p. less than .005) but did not differ on any other smoking topography measure. These data suggest that simple topography measures of puff number and duration may not contribute to between subject differences in tobacco smoke exposure, and that greater attention should be given to more refined measures such as puff volume and depth of inhalation. These data also suggest that the measurement of CO boost per cigarette may provide useful information regarding tobacco smoke intake.     

Smoking environment cues reduce ability to resist smoking as measured by a delay to smoking task

Introduction: Environments associated with smoking may promote lapse and relapse in smokers attempting to quit. Here we examined the effects of exposure to visual smoking environment cues on smoking urge and the ability to resist smoking, as measured with a delay-to-smoking task in which monetary contingencies are provided for resisting smoking. Methods: Adult daily smokers (n = 22) completed two experimental sessions, each following 6 h smoking abstinence. Sessions differed only in the type of cue participants were exposed to (smoking environments vs. nonsmoking environments). Participants completed subjective ratings of smoking urge, withdrawal and other reactions (i.e. craving, affect). Behavioral outcomes on the delay-to-smoking task included latency to first cigarette, number of cigarettes smoked and average number of puffs per cigarette. Results: Across cue exposure sessions, 64% of participants initiated smoking (no effect of condition was observed). However, exposure to smoking environments as compared to the nonsmoking environments resulted in greater craving, faster initiation of smoking, and more smoked cigarettes. Greater craving was associated with a shorter time to initiate smoking, but this effect did not differ across sessions. In contrast, withdrawal was more strongly associated with number of cigarettes smoked during smoking environment sessions. Conclusion: Together, these results suggest smoking environments increase smoking urge and promote smoking behavior. Further research is necessary to examine the specific and interactive effects of smoking-related environments on real-world smoking lapse and relapse.     

Effects of nicotine on cooperative responding among abstinent male smokers

The effects of nicotine on human cooperative responding in abstinent male smokers were examined. During episodes occurring at random times through a session, concurrently available cooperative and independent responses were maintained by points exchangeable for money. Cooperative responses simultaneously added points to counters marked "Your Earnings" and "Other's Earnings" only if the subject's and another person's responses ostensibly coincided. Independent responses added points only to the counter marked "Your Earnings". After the first daily session abstinent subjects smoked ad libitum, received either 0, 2 or 4mg nicotine gum or abstained from smoking. Increases from this first session in time allocated to the cooperative response option, proportion of cooperative responses and cooperative response rate were significantly greater following ad libitum smoking or acute administration of 4mg nicotine. No effects of nicotine abstinence were observed on independent response rate. These results suggest effects on sociability may maintain nicotine use and increase relapse risk in abstinent smokers.     

Alcohol and the reward value of cigarette smoking

People who drink alcohol are more likely to smoke, and experiments have shown that alcohol can increase cigarette smoking. However, it is not clear why alcohol consumption should increase smoking. To address this issue the current experiment looked at the effects of alcohol on a range of behavioural and subjective measures intended to assess the reward value of smoking. These included a preference test carried out after subjects had smoked cigarettes of one colour after consuming alcohol, and cigarettes of another colour after consuming non-alcoholic drinks. In the preference test, subjects were offered the choice of smoking the alcoholic or non-alcoholic drink-paired cigarette. It was hypothesised that if alcohol increased the reward value of smoking, subjects would choose to smoke the alcohol-paired cigarette. Consumption of alcohol increased the length of time people spent smoking, increased the number of puffs taken on each cigarette, and increased the amount of tobacco burnt. There were also strong subjective effects, with subjects looking forward more to smoking after alcohol and reporting greater smoking satisfaction after alcohol. However, subjects did not show a preference for the cigarettes they had smoked after alcohol.     

Effects of graded smoke inhalation on subsequent cigarette smoking behavior

Five smokers smoked a cigarette ad libitum one minute after inhaling either 0, 2, 4, 8 or 12 puffs of tobacco smoke according to a standardized smoking regimen. Heart rate and expired air carbon monoxide levels increased in a linear manner with increasing number of pretreatment puffs. Subjects took fewer puffs on, and spent less time smoking, and puffing on, the cigarette as the number of pretreatment puffs increased. The duration of individual puffs decreased with successive puffs as the cigarette was smoked, but was not affected by the puff pretreatments. Intervals between successive puffs (interpuff intervals) generally increased over the first half, and leveled off or decreased over the second half of the cigarette. Interpuff intervals occurring early in the cigarette tended to increase after the 12-puff pretreatment. The results are consistent with the suggestion that the observed increase in interpuff interval as a cigarette is smoked is the result of a satiation process.