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The effects of nicotine content information on subjective and behavioural responses to nicotine-containing and denicotinized cigarettes
Abstract
The effects of nicotine content information on subjective and behavioural responses to nicotine-containing and denicotinized cigarettes were examined in 30 dependent and 30 nondependent 12-h abstinent smokers. Using the four conditions of a balanced placebo design, participants were given either nicotine-containing cigarettes or denicotinized cigarettes during two laboratory sessions but were told that they received nicotine-containing cigarettes in one session and nicotine-free cigarettes in the other. During each session, participants completed subjective assessments before and after sampling three puffs from the assigned cigarette and were then invited to earn additional cigarette puffs using a computerized progressive ratio task. Regardless of the actual nicotine content, participants self-administered more cigarette puffs when they were told the cigarettes contained nicotine than when told the cigarettes were nicotine-free and tended to show a decrease in craving associated with the intention to smoke after cigarette sampling when told the cigarettes were nicotine-free relative to when they were told the cigarettes contained nicotine. However, regardless of nicotine instructions, participants given nicotine-containing cigarettes showed greater postsampling increases in subjective ratings of 'satisfied' and 'stimulated' than did those given denicotinized cigarettes. The findings suggest that nicotine dose expectancy can affect both subjective and behavioural indices of smoking reinforcement but that the satisfying and stimulating aspects of smoking are related to actual nicotine administration.
... In caffeine studies abstinence was confirmed by a saliva sample (47,59). In nicotine studies abstinence was confirmed by carbon monoxide sample (49,52,53,55,57,60,62). ...
... In placebo group different placebos have been used, a placebo spray which did not contain nicotine but produced sensory irritating effects as those of Nicotrol was used (49), a placebo cigarette with no more than 0.05 mg nicotine and 10 mg of tar (52,53,55), a chewing gum with no nicotine (56), a lozenge which did not contain nicotine (48). After the consumption, they were asked to answer a self-report questionnaire about the perception of being intoxicated (50) or a questionnaire about their beliefs of having consumed an alcohol beverage (54) or estimate how many standard UK units of alcohol had drunk in the study (42,61). ...
... Smokers who were told that nicotine cigarette would impair their performance did not feel these benefits. Darredeau et al. (55) found that the expectancy of receiving nicotine cigarette made participants to try harder to earn cigarette puffs and self-administered them with a higher frequency. Participants who were told that the cigarette did not contain nicotine showed a post-sampling decrease in craving. ...
Objective
The present systematic review aims to analyze the evidence about the influence of placebo effect on craving and cognitive performance in alcohol, caffeine, and nicotine consumers.
Methods
Relevant studies were identified via Pubmed, Web of Science, and Scopus databases (up to March 2020). Only those papers published between 2009 and 2019 were searched.
Results
Of the 115 preliminary papers, 8 studies of database search and 9 of the manual search were finally included in this review. Findings showed that while alcohol expectancies increased craving, caffeine and nicotine expectancies tend to decrease it. Alcohol expectancies caused similar or slower reaction time when alcohol was not consumed, impairments on inhibitory control (especially after alcohol consumption) and similar post-error slowing. The effect of caffeine and nicotine on reaction time has not been elucidated yet, however, caffeine expectancies have been shown to improve accuracy and the attentional filtering of distracting stimuli.
Conclusions
Alcohol, caffeine, and nicotine expectancies play an important role on craving. Although expectancies produce an effect on cognitive performance, caffeine and nicotine beliefs show an ambiguous impact on reaction time. Only the influence of alcohol expectancies on reaction time has been clarified. Furthermore, caffeine beliefs enhance accuracy.
... Smoking blindly administered VLNC cigarettes has been shown to reduce craving as much as smoking regular cigarettes in many (e.g. Baldinger et al., 1995b;Barrett, 2010;Darredeau et al., 2013;Domino et al., 2013;Rose et al., 2010) but not all studies (Baldinger et al., 1995a;Lindsey et al., 2013). Drug stimulus expectancy, or the belief that one has received a pharmacologically active substance, has been shown to elicit responses similar to those elicited by receiving the actual substance (Vogel-Sprott and Fillmore, 1999). ...
... While BPD designs have been used extensively in the alcohol field (Hull and Bond, 1986), adoption in the smoking field was hampered until VLNC cigarettes with tar levels matched to regular cigarettes became available. By our count, seven BPD studies using VLNC and regular cigarettes matched on tar have been published, five between-subjects (Juliano et al., 2011;Juliano and Brandon, 2002;Kelemen and Kaighobadi, 2007;Perkins et al., 2004;Perkins et al., 2008), one mixed between-within design (Darredeau et al., 2013), and one full within-subjects (Gu et al., 2015). Most of these smoking BPD studies investigated the effects of received dose and instructed dose on craving, and one examined the impact of these factors on attentional vigilance (Juliano et al., 2011). ...
... Our cigarette ratings findings are consistent with previous studies that found that study cigarettes containing nicotine were rated as more satisfying (Darredeau et al., 2013) and craving reducing than tar-matched VLNC cigarettes (Benowitz et al., 2006;Hatsukami et al., 2013). These ratings differences are also consistent with many studies that compared VLNC with a usual brand nicotine-containing cigarette in terms of satisfaction (Benowitz et al., 2006;Brauer et al., 2001;Butschky et al., 1995;Gross et al., 1997;Lane et al., 1995) and immediate craving reduction ratings (Baldinger et al., 1995a;Lane et al., 1995). ...
We investigated the effects of acute nicotine dose and expected dose on attentional bias (AB) to smoking and affective cues in overnight nicotine-deprived smokers (n=51; 24 women) using a balanced placebo design, which counterbalanced given nicotine dose (Given-NIC vs. Given-DENIC) with instructed nicotine dose expectancy (Told-NIC vs. Told-DENIC). Before and after smoking a study cigarette, smokers completed a vigilance task where they pressed buttons to every third consecutive even or odd digit, while ignoring intermittent smoking, pleasant, unpleasant, and neutral picture distracters. We examined the early posterior negativity (EPN) and late positive potential (LPP) components of the event-related potentials (ERPs) to the distracters, reaction time (RT) to the target digits, and ratings of the study cigarettes. The EPN was sensitive to both given and instructed nicotine dose, while the instructed dose moderated the impact of given dose for the LPP. The RT metrics were sensitive to given but not to instructed dose. The effects of given dose on ratings following cigarette smoking (e.g. enjoyment) were moderated by the instructed dose. The ERP findings suggest that the anticipated effects of nicotine improve attention much like receiving actual nicotine.
... A subject's belief that he or she is receiving a treatment could lead to observable improvement even in the absence of active drugs. These treatment effects are putatively accomplished by neurobiological processes usually associated with pharmacological actions of active drugs, even though active drugs are not administered (10)(11)(12)(13)(14). Interestingly, beliefs also directly impact behavioral (15)(16)(17)(18)(19)(20) and neurophysiological (21)(22)(23)(24)(25)(26) responses when addictive drugs are administered. Drug dependence is a learned process in which cognitive factors are critical (2,5,(27)(28)(29)(30). ...
... Interestingly, one PET study found that negative drug prediction errors (i.e., alcohol expected but not delivered) decreased striatal DA concentrations while positive drug prediction errors (i.e., alcohol not expected but delivered) increased striatal DA levels in individuals with alcohol dependence (21), which is consistent with our finding of modifiable striatal responses by beliefs. Furthermore, our findings extend previous results showing the impact of beliefs on behavioral performances and subjective states related to nicotine intake (15)(16)(17)20) by detailing the specific neural and computational mechanisms underlying the impact of beliefs on drug effects. These selective effects demonstrate that belief can modulate model-based parameters important for learning and suggest that belief serves as an important cognitive mechanism in addiction. ...
... Additionally, six parameters generated during motion correction were entered as covariates. In the first GLM, market value r t was entered as parametric regressors at the fifth regressor (market price reveal of rounds [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]; in the second GLM, reward prediction error TD t was entered as parametric regressors at the fifth regressor (market price reveal of rounds [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Regressors were orthogonalized in a standard SPM8 fashion. ...
Significance
Nicotine is the primary addictive substance in tobacco, which stimulates neural pathways mediating reward processing. However, pure biochemical explanations are not sufficient to account for the difficulty in quitting and remaining smoke-free among smokers, and in fact cognitive factors are now considered to contribute critically to addiction. Using model-based functional neuroimaging, we show that smokers’ prior beliefs about nicotine specifically impact learning signals defined by principled computational models of mesolimbic dopamine systems. We further demonstrate that these specific changes in neural signaling are accompanied by measurable changes in smokers’ choice behavior. Our findings suggest that subjective beliefs can override the physical presence of a powerful drug like nicotine by modulating learning signals processed in the brain’s reward system.
... In addition to the nicotine's psychoactive reinforcing effects and sensory enjoyment that smokers may obtain from smoking, smoking outcome expectancies likely moderate and/or mediate the onset and maintenance of smoking [74,75]. The need for placebo control in drug outcome studies is predicated on the assumption that drug outcome expectancies may mimic pharmacological effects. ...
... In the case of nicotine, smoking placebo cigarettes causes physiological, subjective and behavioral responses isodirectional with the effects of smoking regular cigarettes. For example, Darredeau and colleagues found that, regardless of nicotine content, nicotinedeprived smokers took more cigarette puffs when they were told they were smoking nicotine-active cigarettes than nicotine-free cigarettes [74]. In addition, among those told they would be smoking nicotine-active cigarettes, participants reported similar levels of satisfaction, stimulation and "high" regardless of the nicotine content of the cigarettes they smoked. ...
How people become addicted to cigarette smoking and remain addicted despite repeated attempts to quit requires piecing together a rather complex puzzle. The present review contextualizes the role of nicotine and smoking sensory stimulation on maintaining smoking, describe nicotine's effects on feeding behavior and body weight, and explore the impact of smoking outcome expectancies, including the belief that nicotine suppresses appetite and body weight on the decision to smoke or vape (use of e-cigarettes). The analysis concludes with a review of rat models of human nicotine intake that attempt to isolate the effects of on appetite and weight gain. This research replicates with relative closeness phenomena observed in smokers, but the rat model falls short of replicating the long-term weight gain observed postsmoking cessation.
... Second, to ensure that the nicotine inhalers would be well tolerated, and that participants' smoking status would remain stable, the protocol required that participants be daily smokers with no immediate intentions to quit. However, heaviness of smoking and quit intentions have been shown to impact nicotine and expectancy-related responses (Darredeau et al., 2013;Schlagintweit et al., 2017). Thus, it is possible that some of the reported findings may not generalize to all smokers. ...
... Further, the present study was underpowered to examine sex differences, which are important to consider when evaluating drug and placebo responses. There is evidence to suggest that men may be more sensitive to the reinforcing effects of nicotine relative to women (Cosgrove et al., 2014;Faulkner et al., 2018;Perkins et al., 1999;Perkins and Karelitz 2015) but that women may be more sensitive to expectancy-related effects relative to men (Darredeau et al., 2013;Perkins et al., 2006). It is possible that sex differences also exist in rsFC associated with actual and perceived nicotine administration, and that a larger sample size would generate adequate statistical power to evaluate such differences. ...
Background: Changes in resting state functional connectivity between the insula and dorsal anterior cingulate cortex as well as between the insula and nucleus accumbens have been linked to nicotine withdrawal and/or administration. However, because many of nicotine’s effects in humans appear to depend, at least in part, on the belief that nicotine has been administered, the relative contribution of nicotine’s pharmacological actions to such effects requires clarification.
Aims: The purpose of this study was to examine the impacts of perceived and actual nicotine administration on neural responses.
Methods: Twenty-six smokers were randomly assigned to receive either a nicotine inhaler (4 mg deliverable) or a nicotine-free inhaler across two sessions. Inhaler content instructions (told nicotine vs told nicotine-free) differed across sessions. Resting state functional connectivity between sub-regions of the insula and the dorsal anterior cingulate cortex and nucleus accumbens was measured using magnetic resonance imaging before and after inhaler administration.
Results: Both actual and perceived nicotine administration independently altered resting state functional connectivity between the anterior insula and the dorsal anterior cingulate cortex, with actual administration being associated with decreased resting state functional connectivity, and perceived administration with increased resting state functional connectivity. Actual nicotine administration also contralaterally reduced resting state functional connectivity between the anterior insula and nucleus accumbens, while reductions in resting state functional connectivity between the mid-insula and right nucleus accumbens were observed when nicotine was administered unexpectedly. Changes in resting state functional connectivity associated with actual or perceived nicotine administration were unrelated to changes in subjective withdrawal and craving. Changes in withdrawal and craving were however independently associated with resting state functional connectivity between the nucleus accumbens and insula.
Conclusions: Our findings highlight the importance of considering non-pharmacological factors when examining drug mechanisms of action.
... Although smokers without ADHD also report these effects [18], smokers with ADHD report stronger effects [16,17] and report that cigarette puffs are more satisfying and better "liked" [17]. Nicotine, the primary psychoactive component of tobacco [19], appears to mediate the impact of smoking on cognition and affect [18,[20][21][22][23]. Collectively, these findings suggest a strong, potentially nicotine-mediated impact of tobacco use on the behavior and cognition of smokers with ADHD. ...
... To the extent that nicotine-induced behavioral suppression reflects the aversive properties of nicotine [28], these results suggest that the adult SHR model of ADHD is less responsive to these aversive properties. This finding is consistent with differences in the nicotine-dependent rewarding and mood-altering effects of smoking between individuals with and without ADHD [17,20,23]. It thus appears that the SHR is a useful model to investigate the neurobiological basis of such differential effects, constituting a much-needed preclinical tool for the study of individual differences in responsiveness to nicotine [65]. ...
Attention deficit hyperactivity disorder (ADHD) is associated with increased risk of tobacco dependence. Nicotine, the main psychoactive component of tobacco, appears to be implicated in ADHD-related tobacco dependence. However, the behavioral responsiveness to nicotine of the prevalent animal model of ADHD, the spontaneously hypertensive rat (SHR), is currently underinvestigated. The present study examined the activational effects of acute and chronic nicotine on the behavior of adult male SHRs, relative to Wistar Kyoto (WKY) controls. Experiment 1 verified baseline strain differences in open-field locomotor activity. Experiment 2 tested for baseline strain differences in rotational behavior using a Rotorat apparatus. Adult SHR and WKY rats were then exposed to a 7-day regimen of 0.6 mg/kg/d s.c. nicotine, or saline, prior to each assessment. A separate group of SHRs underwent similar training, but was pre-treated with mecamylamine, a cholinergic antagonist. Nicotine sensitization, context conditioning, and mecamylamine effects were then tested. Baseline strain differences were observed in open-field performance and in the number of full rotations in the Rotorat apparatus, but not in the number of 90° rotations or direction changes. In these latter measures, SHRs displayed weaker nicotine-induced rotational suppression than WKYs. Both strains expressed nicotine-induced sensitization of rotational activity, but evidence for strain differences in sensitization was ambiguous; context conditioning was not observed. Mecamylamine reversed the effects of nicotine on SHR performance. These findings are consistent with the hypothesis that a reduced aversion to nicotine (expressed in rats as robust locomotion) may facilitate smoking among adults with ADHD.
... Nicotine administration and expectancy components of acute tobacco smoking were independently associated with an immediate reduction in intention to smoke and an increase in ratings of subjective liking of the cigarettes, while nicotine administration alone was associated with reduced withdrawal-related craving. Consistent with these findings, Darredeau and Barrett (2010) demonstrated that nicotine content instructions associated with inhaler use led to reduced intention to smoke but not withdrawalrelated craving, while Darredeau et al. (2013) found that nicotine-containing, but not denicotinized, cigarette smoking was associated with reduced withdrawal-related craving, while expectancy manipulations had no impact. Taken together, these findings suggest that both psychological and pharmacological manipulations may impact the rewarding aspects of smoking behavior, yet pharmacological manipulations may be necessary to impact withdrawal and negative reinforcement. ...
... However, the observed nicotine effects and increased heart rate following nicotine-containing cigarette administration suggest a pharmacologically active dose. In addition, the same brand of nicotine-containing cigarettes have been previously shown to reduce withdrawal-related craving and increase subjective satisfaction and stimulation compared to denicotinized cigarettes, suggesting that they have sufficient nicotine to yield prototypical smoking effects (Barrett, 2010;Darredeau et al., 2013). It is possible, however, that consumption of participants' preferred brand of cigarettes may have been more effective in preventing cue-induced craving. ...
Background: Smoking cessation aids appear to be limited in their ability to prevent craving triggered by exposure to smoking-associated stimuli;
however, the extent to which cue-induced cravings persist following denicotinized or nicotine-containing tobacco smoking is not known.
Methods: Thirty (17 male) ⩾12-hour abstinent dependent smokers completed two sessions during which they smoked a nicotine-containing or
denicotinized cigarette. Instructions regarding the nicotine content of the cigarette varied across sessions, and all participants were exposed to a
neutral cue followed by a smoking cue after cigarette consumption. Craving was assessed before and after cigarette consumption and cue exposure.
Results: Reduced intentions to smoke were associated with both nicotine expectancy (p<0.05) and nicotine administration (p<0.01), while reduced
withdrawal-related craving was uniquely associated with nicotine administration (p<0.05). Smoking-associated stimuli increased craving regardless of
nicotine expectancy or administration (p-values<0.001).
Conclusions: While both nicotine pharmacology and expectancy appear to contribute to craving reduction associated with acute tobacco smoking,
neither smoking-related nicotine administration nor expectation prevents increases in craving following exposure to smoking-associated stimuli. These
findings suggest that cue-induced craving may be resistant to various pharmacological and psychological interventions.
... Finally, Darredeau et al. (2013) examined the effects of nicotine dose (0.6 mg vs <0.05 mg) and nicotine content instructions a Including only the balanced placebo design cells. b Only in the positive mood condition. ...
... Interestingly, most studies involving the administration of denicotinized cigarettes did include a manipulation check, and in most cases the believability of instructions appeared to be considerably higher than in the study by Perkins et al. (2009) mentioned above (Darredeau et al., 2013;Juliano and Brandon, 2002;Juliano et al., 2011;Keleman and Kaighobadi, 2007;Perkins et al., 2004). It is noteworthy that the one exception to this (Perkins et al., 2008) also used a protocol that assigned participants to identical instruction and pharmacology conditions over two sessions, suggesting that such protocols may be less amenable to successful deception. ...
The placebo effect of a psychoactive drug can be defined as the effect of expecting the drug in the absence of its pharmacological actions. As nicotine is widely believed to be the primary factor driving cigarette smoking, smokers are likely to expect nicotine to alleviate craving and withdrawal. The present review examines the extent to which any observed effects of nicotine, and especially its craving- and withdrawal-reducing effects, can be attributed to placebo. We begin by reviewing studies that examined the placebo effects of nicotine in the laboratory and follow with a review of potential placebo effects that are typically not controlled in placebo-controlled studies of nicotine replacement therapy (NRT). In laboratory studies, nicotine instructions decrease tobacco smoking, craving and/or withdrawal, while nicotine-specific effects have not been consistently reported. In field trials of NRT, there is a general failure to assess smokers’ beliefs regarding their drug assignment. This omission makes it difficult to unequivocally attribute findings of placebo-controlled NRT studies to the physiological effects of nicotine. In sum, our review indicates that the placebo effects of nicotine, and specifically nicotine content expectations, may account for many of the benefits associated with nicotine delivery devices in both laboratory and field studies.
... Studies comparing full nicotine and "denicotinized" cigarettes have generally found that cigarettes expected to have no nicotine are less reinforcing and offer fewer positive subjective effects irrespective of actual dose (e.g., Darredeau et al., 2013;Kelemen and Kaighobadi, 2007;Perkins et al., 2008). Important to note is that these studies typically used the Quest 3 brand as a denicotinized cigarette. ...
Current FDA plans include proposed nicotine reduction mandates by the end of 2023. Most research on reduced nicotine cigarettes has been dose-blinded, while a mandate would be known to the public. Few laboratory studies have examined specifically how low nicotine content labeling impacts behavioral response. The purpose of this within-subject, balanced-placebo, human laboratory study was to evaluate the main and interactive effects of nicotine dose expectancy and dose reduction on cigarette reinforcement, withdrawal alleviation, and puff topography.
Participants who smoke daily (N=21; 9 female) completed one practice and four experimental sessions in which expectancy (labeled “average” versus “very low” nicotine) and nicotine dose (0.80 mg versus 0.03 mg yield) were manipulated. Participants in acute withdrawal sampled experimental cigarettes followed by withdrawal alleviation and puff topography measures. Cigarette demand was measured using an incentivized purchase task. Analyses evaluated main and interactive effects of expectancy and nicotine dose.
Nicotine dose manipulation produced expected physiological effects (e.g., heart rate increases) and both reduced nicotine dose and expectation manipulations reduced perceived nicotine content. Expectation of reduced nicotine alone or in combination with reduced nicotine dose did not alter demand, withdrawal alleviation, or topography. Effective withdrawal alleviation was observed in all conditions.
These data inform nicotine regulation policy by suggesting limited compensatory harms caused by reduced nicotine expectations. The minimal acute effects of reduced nicotine expectancy or exposure on demand suggests that reduced nicotine standards are likely to generate their greatest public health benefit through the slowing of newly initiating cigarette smoking.
... The total number of self-administered puffs during the PR task was recorded. Number of self-administered puffs during similar PR tasks have been sensitive to changes in craving (Willner, Hardman, & Eaton, 1995), pharmacological manipulations (Barrett, 2010), and smoking status (Darredeau, Stewart, & Barrett, 2013). ...
Negative reinforcement mechanisms, wherein individuals smoke at regular intervals to ameliorate craving and withdrawal, are integral to persistent smoking. This is consistent with the behavior of dependent smokers but does not fully account for the behavior of intermittent smokers, who do not smoke enough to maintain steady nicotine levels. This study examined the independent and combined impacts of nicotine and tobacco consumption on cigarette craving, withdrawal, and subsequent smoking behavior in 18 nondependent light and intermittent smokers (LITS) and 23 daily, dependent smokers (DDS). Participants administered conventional nicotine-containing cigarettes (NC; 18.9 mg nicotine; 1.41 mg deliverable), reduced nicotine content cigarettes (RNC; 0.4 mg nicotine, 0.05 mg deliverable), nicotine inhalers (NI; 10 mg nicotine, 4 mg deliverable), or nicotine-free inhalers (NFI) across 4 sessions following overnight abstinence. Participants rated craving and withdrawal before and after product administration, then completed a cigarette self-administration task. For cigarette self-administration, neither smoking status nor product affected latency to initiate smoking; however, LITS were more likely to abstain from smoking and administered fewer puffs than DDS. Across participants, pharmacologically active products (NC, RNC, NI) were associated with fewer cigarette puffs than the NFI. For subjective measures, only cigarettes (NC, RNC) reduced craving in both LITS and DDS. NC, RNC, and NI reduced withdrawal in DDS, while withdrawal remained at floor levels across time points among LITS. While subjective ratings and smoking behavior were largely comparable across LITS and DDS, differing patterns of withdrawal symptoms suggest that dependent smoking is motivated by negative reinforcement while nondependent smoking is not.
... Moreover, drug expectancies can significantly enhance, and even override powerful active drug responses ( Bingel et al., 2011 ;Colloca et al., 2004 ;Enck et al., 2013 ;Faria et al., 2017 ;Schedlowski et al., 2015 ). Similarly, expectancies of nicotine content have shown to impact smokers' subjective responses and smoking behaviors ( Mercincavage et al., 2017( Mercincavage et al., , 2016Perkins et al., 2003 ) irrespective of the actual nicotine content ( Dar et al., 2005 ;Darredeau and Barrett, 2010 ;Darredeau et al., 2013 ;Fucito et al., 2016 ;Palmer and Brandon, 2018 ) stressing the critical role of cognitive factors and the relevance of instructional effects in nicotine dependence. ...
Expectancies of nicotine content have been shown to impact smokers' subjective responses and smoking behaviors. However, little is known about the neural substrates modulated by verbally induced expectancies in smokers. In this study we used functional magnetic resonance imaging (fMRI) to investigate how verbally induced expectations, regarding the presence or absence of nicotine, modulated smokers' neural response to a nicotine-free odor. While laying in the scanner, all participants (N = 24) were given a nicotine-free odor, but whereas one group was correctly informed about the absence of nicotine (control group n = 12), the other group was led to believe that the presented odor contained nicotine (expectancy group n = 12). Smokers in the expectancy group had significantly increased blood-oxygen-level-dependent (BOLD) responses during the presentation of the nicotine-free odor in the left ventral tegmental area (VTA), and in the right insula, as compared to smokers in the control group (Regions of interest analysis with pFWE-corrected p ≤ 0.05). At a more liberal uncorrected statistical level (p-unc ≤ 0.001), increased bilateral reactivity in the dorsolateral prefrontal cortex (dlPFC) was also observed in the expectancy group as compared with the control group. Our findings suggest that nicotine-expectancies induced through verbal instructions can modulate nicotine relevant brain regions, without nicotine administration, and provide further neural support for the key role that cognitive expectancies play in the cause and treatment of nicotine dependence.
... Prior studies of nicotine dose expectancies demonstrate that smokers generally respond negatively to cigarettes that they expect have no nicotine, regardless of actual nicotine content. [22][23][24][25] As such, a policy informing smokers that cigarettes contain "reduced" or "low" nicotine content may adversely bias responses to these products, although further research is needed. Studies evaluating "very low" nicotine content expectancies are particularly critical, as the FDA cannot reduce nicotine content to zero. ...
Objectives: We sought to determine if negative responses to reduced nicotine content (RNC) cigarettes during open-label trials result from smokers’ (negative) expectancies. We examined the effects of nicotine content description – independent of actual nicotine content – on subjective responses (craving reduction, withdrawal suppression, mood changes, and sensory ratings) and smoking behaviors (topography measures and carbon monoxide [CO] boost).
Methods: Thirty-six 12-hour-abstinent daily smokers completed a 3-session crossover trial. During each session, participants smoked their preferred brand cigarette – blinded and described as containing “usual,” “low,” and “very low” nicotine content – through a topography device and completed CO and subjective response assessments.
Results: Although nicotine content was identical, compared to the “usual” content cigarette, participants experienced less craving reduction after smoking the “very low” nicotine cigarette, and rated its smoke as weaker (p < .05). Participants took shallower puffs of the “low” nicotine cigarette (p < .05), and rated the “low” and “very low” nicotine cigarettes as weaker and too mild (p < .01).
Conclusions: Negative responses to RNC cigarettes may be due, in part, to negative expectancies about using cigarettes containing less nicotine. In this context, RNC cigarette marketing and labeling are likely important considerations if a federal nicotine reduction policy is initiated.
... Measures of latency (duration in seconds to initiate the first puff), total number of selfadministered puffs and breakpoint (number of key presses to earn the final puff) were collected. Similar PR tasks have been shown to be sensitive to nonpharmacological manipulations in chippers (Darredeau et al., 2013). ...
Tobacco use in nondependent smokers (i.e. chippers) is
believed to be largely determined by situational factors
including social context. However, little empirical research
has examined how different social contexts impact
chippers’ smoking behaviour. Twenty-eight (16 men)
chippers completed two laboratory sessions where they
were offered an opportunity to self-administer puffs of their
preferred tobacco brand in a progressive ratio task. During
an individual session, participants self-administered
cigarettes alone and during a paired session, they selfadministered
cigarettes with a coparticipant who was also
smoking. The strongest predictors for number of selfadministered
puffs and breakpoint during the paired
session were coparticipants’ number of puffs and
breakpoint, respectively (P<0.001), followed by puffs taken
and breakpoint during the individual session (P<0.01).
Current smoking frequency (cigarettes/week) did not
significantly predict puffs taken or breakpoint during the
paired session. Latency to cigarette self-administration
during the paired session was correlated positively with coparticipants’ latency (P<0.05), but not latency during the
individual session or cigarettes per week. The findings
suggest that the presence of another smoker exerts an
important influence on the quantity of chippers’ smoking
behaviour, such that chippers match their smoking
behaviour to that of other smokers in their proximate
environment.
... In contrast to findings that nicotine content instructions affect tobacco cigarette self-administration (Darredeau, Stewart, & Barrett, 2013), in the present study the amount self-administered was not significantly impacted by instructions. Although nicotine-free e-cigarettes mimic many of the sensory-motor properties of conventional cigarettes, they are devoid of various constituents found in tobacco smoke that might interact with nicotine content beliefs to impact smoking behavior (Dar & Barrett, in press). ...
Human research of nicotine and tobacco effects demonstrates that non-pharmacological factors may systematically affect responses to administered substances and inert placebos. Failure to measure or manipulate these factors may compromise study reliability and validity. This is especially relevant for double-blind placebo-controlled research of nicotine, tobacco, and related substances. In this article, we review laboratory-based human research of the impact of non-pharmacological factors on responses to tobacco and nicotine administration. Results suggest that varying beliefs about drug content and effects, perceptions about drug use opportunities, and intentions to cease drug use systematically alter subjective, behavioral, and physiological responses to nicotine, tobacco, and placebo administration. These non-pharmacological factors should be considered when designing and interpreting the findings of human research of nicotine and tobacco effects, particularly when a double-blind placebo-controlled design is used. The clinical implications of these findings are discussed, and we propose methodological strategies to enhance the reliability and validity of future research.
Implications
Growing research demonstrates that non-pharmacological factors systematically alter responses to acute nicotine, tobacco, and placebo administration. Indeed, varying beliefs about nicotine and/or tobacco administration and effects, differing perceptions about nicotine and/or tobacco use opportunities, and inconsistent motivation to quit smoking have been found to exert important influences on subjective, physiological, and behavioral responses. These variables are infrequently measured or manipulated in nicotine and tobacco research, which compromises the validity of study findings. Incorporating methodological strategies to better account for these non-pharmacological factors has the potential to improve the quality of addiction research and treatment.
We examine and refine the Fagerström Tolerance Questionnaire (FTQ; Fagerström, 1978). The relation between each FTQ item and biochemical measures of heaviness of smoking was examined in 254 smokers. We found that the nicotine rating item and the inhalation item were unrelated to any of our biochemical measures and these two items were primary contributors to psychometric deficiencies in the FTQ. We also found that a revised scoring of time to the first cigarette of the day (TTF) and number of cigarettes smoked per day (CPD) improved the scale. We present a revision of the FTQ: the Fagerström Test for Nicotine Dependence (FTND).
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.
In the study, the authors examined the effects of smoking deprivation, anticipation of smoking, and actual smoking on the craving to smoke. Flight attendants who were light to heavy smokers rated their craving to smoke at predetermined time points during a 2-way short flight (each leg 3-5.5 hr) and a 1-way long flight (8-13 hr). In both short and long flights, craving increased gradually and peaked as landing approached. Craving levels at the end of the 1st leg of the short flights were equal to those at the end of the long flight and were much higher than those at the parallel time point in the long flight. In the short flight, craving levels at the beginning of the 2nd leg dropped relative to the end of the 1st leg, both for participants who smoked during the intermission and for those who did not, though the drop was steeper for the former. The results provide additional evidence for the role of psychological factors in determining the craving to smoke in a naturalistic setting.
We recently showed effects of nicotine dose and nicotine expectancy on some responses to cigarette smoking, with generally no influence of induced mood on these effects. The present study extended this line of research to Nicotrol nasal spray, to determine whether formulation (spray vs. smoking) alters responses.
Smokers abstained overnight before each of two virtually identical sessions, involving negative or positive mood induction. They were randomized to one of five groups, four comprising the 2 x 2 balanced placebo design, varying actual and expected dose of nicotine in the nasal spray, and the fifth group a no-spray control. Dependent measures included self-reported affect, craving, withdrawal, and spray ratings of "liking" and "how much nicotine." Analyses were limited to those whose nicotine expectancies were manipulated successfully (N = 48).
The following results matched those from our smoking study: expecting nicotine increased liking; expected, but not actual, nicotine dose increased dose perception; neither actual nor expected nicotine dose had much influence on affect or withdrawal; and mood had no influence on these effects. However, both actual and expected nicotine dose decreased craving in response to spray, contrary to our prior study with smoking.
Formulation made little difference in some effects of nicotine and expectancies, but other effects differed by formulation. Some of these findings, particularly for craving reduction, may have implications for enhancing the acute therapeutic effects of nasal spray and, perhaps, other medications in smokers trying to maintain abstinence after quitting.
We examine and refine the Fagerström Tolerance Questionnaire (FTQ: Fagerström, 1978). The relation between each FTQ item and biochemical measures of heaviness of smoking was examined in 254 smokers. We found that the nicotine rating item and the inhalation item were unrelated to any of our biochemical measures and these two items were primary contributors to psychometric deficiencies in the FTQ. We also found that a revised scoring of time to the first cigarette of the day (TTF) and number of cigarettes smoked per day (CPD) improved the scale. We present a revision of the FTQ: the Fagerström Test for Nicotine Dependence (FTND).
To determine the relative effects of expectancy and nicotine depletion on aversive withdrawal symp- toms, we gave 109 smokers attempting to quit either nicotine gum or placebo within a balanced placebo design and monitored their withdrawal symptoms and smoking for 2 weeks . Subjects who believed they were getting nicotine gum reported less physical symptoms of withdrawal, showed less arousal, and smoked fewer cigarettes during the first week of quitting when compared with those who thought they were tticxiving placebo gum . The actual nicotine content of gum had no effect on withdrawal or relapse .
A brief, 10-item version of the Questionnaire of Smoking Urges (QSU; Tiffany & Drobes, British Journal of Addiction 86:1467-1476, 1991) was administered to 221 active cigarette smokers in a laboratory setting (Study 1) and to 112 smokers enrolled in a comprehensive smoking cessation program (Study 2). In the laboratory setting, craving to smoke was evaluated in response to neutral and smoking-related stimuli. In the clinical setting, craving was assessed prior to cessation and again during treatment. Factor analyses revealed that a two-factor solution best described the item structure of the QSU-Brief across conditions. Factor 1 items reflected a strong desire and intention to smoke, with smoking perceived as rewarding for active smokers. Factor 2 items represented an anticipation of relief from negative affect with an urgent desire to smoke. The findings were consistent with the expressions of craving found in the 32-item version of the QSU (Tiffany & Drobes, 1991). Regression analyses demonstrated stronger baseline mood intensity and self-reported tendency to smoke to achieve pleasurable effects and to experience the desire to smoke when cigarettes are unavailable were predictive of general levels of craving report in active smokers in the laboratory and clinical setting. The findings supported a multidimensional conceptualization of craving to smoke and demonstrated the utility of a brief multidimensional measure of craving.
Subjective and reinforcing effects of smoking a cigarette were examined within a 2 x 2 modified balanced-placebo design, which manipulated instructions about nicotine content (i.e., told regular nicotine vs. told low nicotine) and actual nicotine dose (given a regular nicotine brand vs. a denicotinized brand). Most ratings of the nicotine content and reward value of cigarettes were higher for those told regular nicotine versus told low nicotine, and for those given regular nicotine versus given low nicotine. Nicotine and instructions did not affect craving, withdrawal, or smoke-reinforced responding, but instructions affected the number of puffs earned for those given low nicotine (i.e., placebo effect). Thus, verbal information (instructions) can influence some responses to smoking consistent with the presence of placebo and antiplacebo effects.
Compared to men, the smoking behavior of women may be less responsive to nicotine and more responsive to nonpharmacological factors, perhaps including verbal information (e.g., dose instructions).
This study compared the influence of the presence vs absence of dose instructions on the subjective and reinforcing effects of nicotine via cigarette smoking in men and women.
Subjects (n=120) abstained overnight from smoking and were randomly assigned to one of four groups. Half of the subjects received nicotine cigarettes (Quest 1, yield of 0.6 mg), and the other half received denicotinized cigarettes ("denic"; Quest 3, yield of 0.05 mg). Furthermore, half of each subsample was accurately instructed they were receiving a "normal nicotine" or a "no nicotine" cigarette, while the other half received no instructions. Subjects completed baseline measures of craving and mood (positive and negative affect), took two puffs from the cigarette after receiving dose instructions or no instructions, and then rated the cigarette's "reward" value (liking, satisfying) and other characteristics. They also repeated the craving and mood measures. Subjects then smoked more of that same brand ad libitum over the next 30 min to measure reinforcement (puff number and latency to first puff).
Overall, nicotine increased reward, other cigarette ratings, and positive affect, but did not affect craving or smoking behavior. However, results varied by sex. Dose instructions enhanced the effects of nicotine on smoking reward and reinforcement in women, while instructions tended to dampen or even reverse these effects of nicotine in men (i.e., interaction of sex x nicotine x instructions).
In women but not in men, the influence of nicotine on smoking reward and reinforcement is enhanced by accurate verbal information about the cigarette's nicotine dose. These results are consistent with the notion that the smoking behavior of women, relative to men, may be more responsive to nonpharmacological factors.
Cues associated with drug taking can trigger relapse, drug seeking, and craving in addicted individuals. Behavioral studies suggest that drug availability and withdrawal can affect the individual response to drug cues. Moreover, the importance of subjective craving in cue-induced relapse has been questioned and an alternative model put forward according to which drug cues trigger habitual drug-seeking behaviors independently of craving. We used functional magnetic resonance imaging to compare the brain response to smoking and control videotapes in 20 healthy smokers, while varying their expectancy to smoke and abstinence levels. The neural response to cigarette cues was strongly modulated by expectancy and, to a lesser extent, abstinence. In people expecting to smoke immediately after the scan, smoking cues activated brain areas implicated in arousal, attention, and cognitive control. However, when subjects knew they would not be allowed to smoke for 4 h, there was almost no brain activation in response to smoking cues, despite equivalent reported levels of craving. In the dorsolateral prefrontal cortex, the neural response was a function of both craving and expectancy. Thalamo-cingulate connectivity, thought to be an index of arousal, was greater during expectancy than nonexpectancy. Our findings confirm the importance of expectancy in the neural response to drug cues, and lend support to the theory that these cues act on brain areas involved in arousal and attention.
Although numerous studies have documented that nicotine can function as an effective reinforcer of intravenous self-administration behavior in animals, it has not been clearly shown to maintain intravenous self-administration behavior above vehicle placebo levels in humans.
To compare the reinforcing effectiveness of nicotine versus saline placebo in human research volunteers responding under fixed-ratio (FR) schedules of intravenous drug self-administration while systematically increasing response requirements.
Eight male cigarette smokers resided in an inpatient research unit. During 3-h sessions, intravenous injections of nicotine and saline were available concurrently and were contingent on responding (pulling a lever). Nicotine dose (0.75, 1.5, 3.0 mg/injection), time out (TO) value after each injection (1-20 min) and FR response requirement (10-1600) were varied in different subjects over consecutive sessions.
Number of nicotine injections/session significantly decreased as dose/injection increased and the number of self-administered nicotine injections was significantly greater than the number of self-administered saline injections across conditions. When FR value was progressively increased over sessions, response rates for nicotine, but not saline, injections increased, with maximal rates at the highest FR values. Rates of responding and injections/session were markedly and significantly higher for nicotine than for saline at FR values of 200 and above. Subjects rated effects of nicotine as both significantly more positive and more negative than saline placebo, with positive ratings significantly higher than negative ratings.
Nicotine functioned as a prototypic drug of abuse, serving as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Subjects adjusted their responding to response requirements in a way that maintained relatively constant levels of nicotine injections per session.
The expectancy and pharmacological effects of nicotine (0.60 mg) on memory and the subjective effects of cigarettes were examined by using a balanced-placebo design (i.e., expect either nicotine or no nicotine and receive either nicotine or no nicotine). A total of 120 college students who smoke were assigned to 1 of the 4 experimental groups, then rated the cigarettes on a number of dimensions and completed questionnaires on smoking urges, tension, and energy. Participants also completed tests of memory as well as predictions of memory. Pharmacology played a stronger role than expectancy in most ratings of the cigarettes, but significant effects of expectancy did emerge for feelings of increased wakefulness, concentration, calming, cigarette satisfaction, and hunger reduction. The presence of nicotine significantly reduced smoking urges, but expectancy alone reduced tension after smoking. Neither variable produced significant effects on memory or memory predictions. These findings demonstrate that nonpharmacological factors can play an important role in the self-reported effects of nicotine.
Smokers have weak positive expectancies for nicotine replacement therapies relative to smoking (Juliano and Brandon, Nicotine Tob Res, 6:569-574, 2004).
This study investigated if a manipulation designed to alter expectancies for the nicotine patch was effective in increasing positive expectancies for the patch and influencing smoking cessation outcomes during a 2-day abstinence period.
Smokers (n = 72) were randomly assigned to receive information that emphasized either patch benefits (n = 25) or standard patch information including side effects (n = 25). Participants wore placebo patches but were told that the patches contained nicotine. A control condition (n = 22) was informed that they received placebo patches while given standard patch information to independently test the effect of the nicotine-dose instructional set on abstinence outcomes.
Benefits information significantly increased positive expectancies for the patch and promoted positive mood during the abstinence period relative to the side effects information. Nicotine-dose instructions resulted in fewer lapsed cigarettes and higher ratings of patch helpfulness than placebo instructions. In particular, women's smoking behavior appeared to be more influenced by nicotine instructions than that of men.
The results of this preliminary study suggest that information provided to smokers about patch effects and nicotine content may influence behavioral and subjective outcomes of patch use.
Acute responses to smoking are influenced by nicotine and by nonpharmacological factors such as nicotine dose expectancy and sensory effects of smoke inhalation. Because negative mood increases smoking reinforcement, the authors examined whether these effects may be altered by mood context. Smokers (n=200) participated in 2 sessions, negative or positive mood induction, and were randomized to 1 of 5 groups. Four groups comprised the 2x2 balanced placebo design, varying actual (0.6 mg vs. 0.05 mg yield) and expected nicotine dose (expected nicotine vs. denicotinized [denic]) of cigarettes. A fifth group was a no-smoking control. Smoking, versus not smoking, attenuated negative affect, as well as withdrawal and craving. Negative mood increased smoking reinforcement. However, neither actual nor expected nicotine dose had much influence on these responses; even those smokers receiving and expecting a denic cigarette reported attenuated negative affect. A follow-up comparison suggested that the sensory effects of smoke inhalation, but not the simple motor effects of smoking behavior, were responsible. Thus, sensory effects of smoke inhalation had a greater influence on relieving negative affect than actual or expected nicotine intake.
Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.
Nicotine intake is a necessary but insufficient factor in maintaining tobacco smoking behavior, and nonpharmacological factors associated with smoking play a key role. Some of these factors may influence smoking behavior by eliciting placebo effects, or responses related specifically to the belief that one is consuming a drug. Greater knowledge of placebo effects of smoking would improve our understanding of factors that maintain smoking behavior, thereby aiding efforts to develop treatments to counter the influence of these factors. In addition, better understanding of placebo effects from other means of nicotine intake could help determine mechanisms of the therapeutic actions of nicotine replacement therapy, perhaps enhancing its efficacy in smoking cessation. Placebo effects of smoking or other nicotine intake have received little research attention. In this review, we first discuss common terms and methods of placebo research, especially the balanced-placebo design. We then examine the limited research directly assessing placebo effects of smoking and other nicotine intake, namely studies that manipulated instructions to subjects about the drug content of an ingested substance. Finally, we examine other studies relevant to gauging the likely magnitude of placebo smoking effects. In an effort to encourage more research on these placebo effects, we pay substantial attention to future directions. Among recommendations are testing the utility of the balanced-placebo design and other rigorously controlled designs, and including multiple measures of placebo effects in addition to self-report. Future research also should explore the moderating influences of the environmental context and of individual difference factors on placebo effects of smoking and other nicotine intake.
Both nicotine and various non-nicotine smoking factors are believed to contribute to tobacco addiction but their relative roles remain incompletely understood. This study aimed to help clarify these roles by examining acute interactions between nicotine and denicotinized tobacco (DT). During two randomized blinded sessions, the effects of a quick-release 4 mg nicotine lozenge (NL) versus placebo lozenge (PL) on the subjective and behavioural responses to DT were examined in 27 (14 men) dependent, daily smokers. Participants were administered NL or PL for 30 min before receiving one initial DT cigarette. Participants could then earn additional DT cigarette puffs over the following 60 min. Subjective state was assessed using the Questionnaire of Smoking Urges-Brief and visual analogue scales at baseline, postlozenge and postinitial DT cigarette. Relative to PL, NL was associated with increased alertness as well as with reduced levels of DT self-administration (P<0.01). The administration of a single DT cigarette was followed by a reduction in craving under both lozenge conditions (P<0.001), an effect that was significantly greater in women (P<0.01). Moreover, DT administration was associated with increased ratings of 'pleasant', 'satisfied', 'stimulated' and 'relaxed', as well as with decreased ratings of 'anxious' (P's<0.01), independent of lozenge condition. The findings suggest that both nicotine and non-nicotine smoking factors may make important contributions towards the addictive properties of tobacco.
Separate and combined effects of nicotine and the nicotinic antagonist mecamylamine were studied in 32 healthy volunteer smokers after overnight abstinence from smoking. Subjects participated in three sessions (3 h each), during which they wore skin patches delivering either 0 mg/24 h, 21 mg/24 h or 42 mg/24 h nicotine. Thirty-two subjects were randomly assigned to two groups receiving oral mecamylamine hydrochloride (10 mg) vs. placebo capsules. Two and one-half hours after drug administration, subjects were allowed to smoke ad lib, rating the cigarettes for rewarding and aversive effects. Transdermal nicotine produced a dose-related reduction in the subjective rewarding qualities of smoking. Nicotine also reduced craving for cigarettes and this effect was attenuated, but not eliminated, by mecamylamine. Mecamylamine blocked the discriminability of high vs. low nicotine puffs of smoke, and increased nicotine intake substantially during the ad lib smoking period. Some of the psychophysiological effects of each drug (elevation in blood pressure from nicotine, sedation and decreased blood pressure from mecamylamine) were offset by the other drug. The results supported the hypothesis that nicotine replacement can alleviate tobacco withdrawal symptoms even in the presence of an antagonist such as mecamylamine. Mecamylamine did not precipitate withdrawal beyond the level associated with overnight cigarette deprivation, suggesting its effects were primarily due to offsetting the action of concurrently administered nicotine as opposed to blocking endogenous cholinergic transmission.
A growing body of evidence suggests that non-pharmacological factors may play an important role in smoking cessation outcomes using nicotine replacement therapies. This study examined the role of information about nicotine content in smokers' subjective responses to nicotine and placebo inhalers, using the four conditions of the balanced-placebo design in a mixed within/between-subjects design.
Twenty-four adult smokers (12 male) completed two laboratory sessions following overnight abstinence from smoking. Participants were randomly assigned to receive either nicotine inhalers or placebo inhalers in both sessions but were told that they received a nicotine-containing inhaler in one session and a nicotine-free inhaler in the other. In each session participants completed subjective assessments before and after inhaler administration using visual analogue scales and the Brief Questionnaire of Smoking Urges.
While neither nicotine content nor information about it significantly affected cigarette craving associated with withdrawal relief, participants reported a greater reduction in craving associated with intention to smoke when told the inhalers contained nicotine than when told the inhalers were nicotine-free, regardless of actual nicotine content.
Findings suggest that psychological factors play an important role in smokers' subjective responses to nicotine inhalers, the effects of which cannot be solely attributed to the direct pharmacological effects of nicotine.
Nicotine and non-nicotine components of cigarette smoke contribute to its reinforcing effects; however, the specific role of each component in maintaining behavior has not yet been elucidated.
To assess the reinforcing effects of nicotine and non-nicotine components of cigarette smoke by presenting a concurrent choice paradigm in which participants had access to intravenous (IV) nicotine infusions vs. saline (placebo) infusions and puffs from denicotinized ("denic") cigarettes vs. air (sham puffs). We also measured the effects on self-administration of prior satiation with each component.
Sixteen smokers participated in seven sessions: 1) a baseline smoking assessment, used to tailor the nicotine dose per infusion; 2) two sessions for training discrimination of IV nicotine vs. saline infusions and denic smoke vs. sham puffs; and 3) four sessions assessing choice behavior after different satiation conditions.
Denic smoke was self-administered more than any other alternative, including IV nicotine. IV nicotine, however, was preferred over IV saline and sham puffs. Preference for denic smoke vs. IV nicotine was inversely correlated with subjective ratings of "comfort" associated with nicotine. Smoke satiation reduced the number of denic puffs taken during choice periods, while prior nicotine administration did not affect puffing behavior. Smoking withdrawal symptoms were alleviated both by nicotine administration and by denic smoke.
In established smokers, non-nicotine aspects of cigarette smoking have potent reinforcing effects. While current smoking cessation pharmacotherapies primarily address the nicotine component of cigarette addiction, future cessation strategies should also be designed to target non-nicotine factors.
The effects of the acute administration of nicotine [through nicotine inhalers (NI) and placebo inhalers (PI)], nicotine-containing tobacco (NT), and denicotinized tobacco (DT), on smokers' subjective responses and motivation to smoke were examined in 22 smokers (12 male, 10 female; 11 low dependent, 11 high dependent). During four randomized blinded sessions, participants self-administered NI, PI, NT, or DT, and assessed their effects using Visual Analogue Scales and the Brief Questionnaire of Smoking Urges. They could then self-administer their preferred brand of cigarettes using a progressive ratio task. NT and DT were each associated with increased satisfaction and relaxation as well as decreased craving relative to the inhalers and NT increased ratings of stimulation relative to each of the other products. Both NT and DT delayed the onset of preferred tobacco self-administration relative to NI and PI but only NT reduced the total amount self-administered. Sex differences were evident in the effects of DT on withdrawal-related cravings with women experiencing greater DT-induced craving relief than men. Findings suggest that DT is effective in acutely reducing many smoking abstinence symptoms, especially in women, but a combination of nicotine and non-nicotine tobacco ingredients may be necessary to suppress smoking behavior.
A brief, 10-item version of the Questionnaire of Smoking Urges (QSU; Tiffany & Drobes, 1991) was administered to 221 active cigarette smokers in a laboratory setting (Study 1) and to 112 smokers entering a comprehensive smoking cessation program (Study 2). In the laboratory setting, craving to smoke was evaluated in response to neutral- and smoking-related stimuli. In the clinical setting, craving was assessed prior to cessation and again during treatment. This brief measure demonstrated high internal consistency across conditions and settings with smokers at different stages of drug use. Factor analyses revealed a two-factor solution best described the item structure of the QSU-Brief across conditions. Factor 1 scale items reflected a strong desire and intention to smoke, with smoking perceived as rewarding for active smokers. Factor 2 scale items represented an urgent desire to smoke with smoking anticipated as negatively reinforcing. These findings are consistent with the expressions of craving found in the long QSU (Tiffany & Drobes, 1991). Multiple regression analyses demonstrated stronger baseline mood intensity and self-reported tendency to smoke to achieve pleasurable effects and to experience the desire to smoke were predictive of craving report in active smokers in the laboratory setting. These predictors also were associated significantly with craving in active smokers in the clinical setting. These findings support a multidimensional conceptualization of craving to smoke and underscore the utility of a multidimensional measure of craving. These studies clearly established the reliability of the QSU-Brief used in the laboratory and clinical settings with active and abstaining smokers.
There are a number of methodological problems with the traditional placebo-controlled design used to investigate the effects of nicotine in human subjects. For example, the experimental instructions may create a 'guessing set' in the participants such that they search for possible clues to try to identify which condition they are in. If they guess correctly, the internal validity of the design may be threatened. Furthermore, by attempting to control for the effect of subjects' expectancies, the traditional placebo design precludes any estimate of expectancy effects. Continued use of this methodology in the smoking field is likely to lead to an overemphasis on pharmacological factors in smoking and a corresponding underemphasis on cognitive factors and nicotine-expectancy interactions. These problems can be overcome by the use of the balanced placebo design which orthogonally manipulates instructions (Told Nicotine versus Told Placebo) and nicotine (Received Nicotine versus Received Placebo). The balanced placebo design offers a powerful methodology for studying many aspects of smoking behaviour and nicotine effects, and three examples are given to illustrate its potential in this field: nicotine titration, nicotine and performance, and priming effects in smoking relapse.
Human volunteers who smoked cigarettes were given the opportunity to press a lever that resulted in intravenous injections of saline or nicotine. Nicotine injections were taken in orderly patterns that were related to unit dose, whereas patterns of saline injections varied widely. Furthermore, the volunteers reported that nicotine produced subjective effects similar to those produced by administration of abuse drugs such as morphine or cocaine.
The balanced placebo design (BPD) was used to evaluate the independent effects of nicotine dose and smoking-related expectancies on self-reported anxiety, urge to smoke, and withdrawal symptoms. After anxious mood was induced, participants smoked either a de-nicotinized cigarette or one with standard nicotine content. Nicotine dose was crossed with instructions that the cigarette was either de-nicotinized or standard. Nicotine cigarettes produced greater anxiety reduction than de-nicotinized cigarettes. Nicotine instructions attenuated anxiety only among those who held relevant expectancies. Nicotine dose and instructional set interacted such that either nicotine cigarettes or instructions that the cigarettes contained nicotine were sufficient to reduce urge to smoke. Implications of these findings and methodological issues regarding use of the BPD with cigarettes are discussed.
A nicotine lozenge was developed as a novel smoking cessation aid. Abuse liability, which in this context refers to use by novices not addicted to tobacco, may be expected to be low for the lozenge due to the relatively slow route of nicotine absorption. However, its resemblance to commercially marketed lozenges and its palatability, intended to increase medication compliance, may increase its abuse liability, especially among younger individuals.
The present study evaluated the abuse liability of the nicotine lozenge. Effects of the lozenge on cigarette craving were also measured.
Subjective and physiological effects of the nicotine lozenge were tested in healthy adult smokers ( n=12, 22-55 years old); a group of younger subjects ( n=12, 18-21 years) was also included to allow for assessment of abuse liability of the lozenge in young adults specifically. Amphetamine and a confectionery lozenge were included in the study conditions as positive controls for abuse liability and palatability, respectively, and nicotine gum was included to allow for comparison with a marketed oral nicotine replacement product with low abuse liability.
The nicotine lozenge did not increase ratings of traditional abuse liability predictors (good effect, like effect, MBG scale of the ARCI), while amphetamine significantly increased ratings on these measures. The lozenge dose dependently decreased craving for cigarettes after 70 min of abstinence, but only in the older group. Palatability of the lozenge was rated lower than a confectionery lozenge, but not lower than nicotine mint gum.
Results suggest that the nicotine lozenge has low abuse liability, both in adults and young adults. The lozenge reduces craving to smoke, although craving reduction may not apply to young adults (18-21 years). Subjective effects of the lozenge are consistent with utility as a smoking cessation aid and are comparable to those of nicotine gum.
Previous studies suggest that craving for cigarettes is substantially influenced by non-nicotine mechanisms such as habits, cues, and expectations. As orthodox Jews must refrain from smoking during the Sabbath, examining their craving levels during this habitual abstinence may be informative in separating smoking deprivation from other determinants of craving and withdrawal.
To examine the extent to which the habitual abstinence of Orthodox Jews during the Sabbath is associated with craving to smoke and with other reactions to smoking abstinence.
Twenty orthodox Jewish heavy smokers were assessed three times: on a workday when smoking as usual, on a Sabbath when they never smoke, and on a forced abstinence workday. Craving, irritability, and other commonly reported smoking withdrawal symptoms were assessed retrospectively at several time points during the preceding 24 h.
Craving to smoke, and to a lesser extent, irritability, was lower during the Sabbath than during the two other test days. Self-reported difficulty in abstaining was also lower on the Sabbath than on the workday. Craving in the evening preceding the test day was always significantly higher than in the next morning, despite the overnight abstinence before the morning assessment.
These results support previous findings in showing that craving to smoke is determined to a large extent by smoking-related habits, cues, and expectations.
Nicotine is almost universally believed to be the primary agent motivating tobacco smoking and the main impediment to cessation. A principal argument in support of the presumed reinforcing properties of nicotine is that smokers self-administer pure nicotine. However, the evidence for nicotine self-administration in smokers has not been critically examined.
To review and examine the empirical basis for the assertion that smokers self-administer pure nicotine.
We reviewed all the studies we were able to locate that are cited as demonstrating self-administration of nicotine, isolated from tobacco, in normal smokers and non-smokers. These studies investigated self-administration of intravenous nicotine, nicotine gum and nicotine spray. Using the authors' own criteria, we examined whether these studies in fact demonstrate nicotine-self administration.
None of the studies we reviewed demonstrated nicotine self-administration in smokers. Both smokers and non-smokers failed to show preference for nicotine over placebo in any of these studies, including in a series of six reports of overnight abstinent smokers having access to nicotine nasal spray, a rapidly absorbed form of nicotine.
The common statement that smokers self-administer pure nicotine lacks empirical support. Smokers in fact do not administer pure nicotine in any of the forms studied to date, even when abstinent and presumably nicotine-deprived. This conclusion necessitates a critical re-examination of the nicotine addiction thesis.
Although nicotine is the main addictive chemical in tobacco, there have been few studies of pure nicotine self-administration in humans. The goal of this study was to test the parameters of an intravenous (IV) nicotine self-administration model using nicotine doses presumed to be within the range of those of average intake from cigarette smoking. Six male and four female smokers participated in a double-blind, placebo-controlled, crossover study, which consisted of one adaptation and three experimental sessions. In each experimental session, subjects were randomly assigned to one of the three doses of nicotine (0.1, 0.4, or 0.7 mg). The lowest nicotine dose, 0.1 mg, was chosen to be approximately half the amount of nicotine inhaled from one puff of a cigarette. During each experimental session, subjects first sampled the assigned nicotine dose and placebo and then had the opportunity to choose between nicotine and placebo for a total of six choices over a 90-min period. Out of six options, the average (SEM) number of nicotine choices were 3.0 (0.48) for 0.1 mg, 4.7 (0.48) for 0.4 mg and 4.5 (0.46) for 0.7 mg, indicating a significant effect of nicotine dose on nicotine choice. Both the 0.4 and 0.7, but not the 0.1 mg, nicotine doses were preferred to placebo. These higher doses also produced increases in heart rate, blood pressure, and ratings of drug liking and high. Overall, these findings indicate that smokers chose both the 0.4 and the 0.7 mg nicotine doses over placebo. Our model may be useful in the evaluation of the effects of both behavioral and pharmacological manipulations on nicotine self-administration in humans.
Mood, nicotine, and dose expectancy effects on acute responses to nicotine spray
- K A Perkins
- A Grottenthaler
- M M Cioccocioppo
- C A Conklin
- M A Sayette
- A S Wilson
Perkins KA, Grottenthaler A, Cioccocioppo MM, Conklin CA, Sayette MA, Wilson
AS (2009). Mood, nicotine, and dose expectancy effects on acute responses
to nicotine spray. Nicotine Tob Res 11:540-546.