Threshold for the pleasurable effects of nicotine are lower than its reinforcing effects during self-administration.

A recent study demonstrated that during a single sampling period, 0.1 mg of intravenous (IV) nicotine (vs. placebo) was found to be the threshold for subjective and physiological drug effects. The present study is a secondary analysis evaluating whether the threshold for subjective and physiological effects is similar when the subject has repeated opportunities to choose blinded doses of nicotine versus placebo. We also examined whether cigarette craving, withdrawal, and rate of nicotine metabolism affected nicotine reinforcement, defined by a greater number of nicotine choices than placebo. Young adult (n = 34; 68% male), daily smokers had five laboratory sessions after overnight abstinence. After sampling an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg/70 kg) versus saline (placebo), participants completed a nicotine self-administration (NSA) procedure that included 10 opportunities to self-administer IV dose of nicotine or placebo. The threshold for subjective positive effects of nicotine during the NSA was equal to or lower than the sampling period, 0.05-0.1 mg versus 0.1 mg. The threshold for nicotine-induced heart rate increase was higher during the NSA than during the sampling period (0.2 mg vs. 0.1 mg). Higher baseline craving and nicotine metabolite ratio (NMR) were associated with nicotine reinforcement at 0.2 mg and 0.1 mg doses, respectively (p < .05). The results suggest that subjective effects during NSA are reported at doses lower than the sampling period. Taken together, tobacco products thought to be subthreshold for reinforcement should be carefully evaluated for their subjective effects, including their discriminative stimulus effects. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Plasma Menthol Glucuronide as a Biomarker for the Behavioral Effects of Menthol and Nicotine in Humans.

This secondary analysis sought to determine if plasma menthol glucuronide (MG) concentrations predict changes in three outcomes, subjective drug effects, urges to smoke, and heart rate, following concurrent inhaled menthol and intravenous nicotine. A total of 45 menthol and non-menthol cigarettes smokers (36 male, nine female, 20 Black, and 23 White) were included in this double-blind, placebo-controlled study. Across three test sessions, participants were assigned to a different flavor condition for each session: 0% (no menthol), 0.5%, or 3.2% menthol. In each test session, participants received in a random order one intravenous delivery of saline and two intravenous deliveries of nicotine (0.25 mg/70 kg and 0.5 mg/70 kg), each 1 h apart, concurrent with menthol delivery by e-cigarettes. The main outcomes were subjective drug effects, urges to smoke, and heart rate. The results showed that following e-cigarette inhalation, changes in plasma MG concentrations or "menthol boost" increased proportionally to the menthol concentration in the e-liquids. While changes in plasma MG concentrations were not predictive of increases in heart rate or subjective drug effects that are reflective of acute effects from nicotine (i.e., feel good effects, stimulated, aversive effects), they were predictive of cooling effect, a typical effect of menthol, but only in menthol smokers in the absence of concurrent active nicotine infusion. These findings demonstrate the utility of plasma MG as a biomarker both for acute menthol exposure by e-cigarette inhalation and for the examination of the concentration-dependent behavioral and physiological effects of menthol in humans.

Impact of delivery rate on the acute response to intravenous nicotine: A human laboratory study with implications for regulatory science.

Faster delivery rate enhances the abuse potential of drugs of abuse, yet systematic studies on the impact of delivery rate on the acute effects of nicotine in humans are lacking. Using an intravenous (IV) nicotine infusion procedure that allows precise control of rate of delivery, we examined the impact of nicotine delivery rate on the positive subjective drug effects, smoking urges, withdrawal, heart rate, blood pressure and attention function in smokers. Twenty-four male and female (ages 21-35) dependent smokers attended five experimental sessions, following overnight abstinence from smoking. Using a crossover design, participants attended five sessions, where they were assigned to a random sequence of saline infusion or 1 mg nicotine delivered over 1, 2.5, 5 or 10 min at rates of 1, 0.4, 0.2 or 0.1 mg/min, respectively. The positive subjective effects of nicotine were most robust under the two faster delivery rate conditions, 1- and 0.4-mg nicotine/min. In contrast, all nicotine delivery rates were equally more effective than saline in alleviating urges to smoke. Likewise, nicotine-induced heart rate increases did not vary with the rate of nicotine delivery. Lastly, the cognitive enhancing effects of nicotine were observed only under the two slowest delivery rate conditions-0.1- and 0.2-mg nicotine/min. Collectively, these findings support the critical role of delivery rate in optimizing nicotine's abuse potential versus potential therapeutic effects and have timely implications for developing novel therapeutics for nicotine dependence, as well as for tobacco regulatory science.

Threshold dose for intravenous nicotine self-administration in young adult non-dependent smokers.

RATIONALE: Reducing nicotine content of inhaled tobacco products may prevent nicotine addiction, but the threshold for nicotine reinforcement has not been systematically evaluated in controlled human laboratory studies. OBJECTIVES: The current study uses a novel double-blind placebo-controlled intravenous (IV) nicotine self-administration (NSA) model to determine threshold for subjective effects of nicotine and nicotine reinforcement using a forced choice self-administration procedure. METHODS: Young adults (n = 34) had 5 laboratory sessions after overnight nicotine abstinence. In each session, participants sampled and rated the subjective effects of an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg nicotine/70 kg bodyweight) versus saline (placebo), then were given a total of 10 opportunities to self-administer either the IV dose of nicotine or placebo. RESULTS: Mixed effect models revealed a significant effect of nicotine dose for positive (i.e., "stimulatory" and "pleasurable"; p < .0001) effects, but not "aversive" effects during sampling period. Post hoc comparisons showed that higher doses (i.e., 0.1 and 0.2 mg) were associated with greater stimulatory, pleasurable, and physiological effects than placebo and lower doses. Mixed effect models revealed that only the highest dose (i.e., 0.2 mg) was consistently preferred over placebo. Sex differences were generally weak (p = .03-.05). CONCLUSIONS: Using our IV nicotine NSA model, the threshold for detecting positive effects of nicotine in young adult smokers is about 0.1 mg, but a higher dose of nicotine, 0.2 mg, is required to produce a consistent nicotine reinforcement. Regarding the regulatory impact, our findings further support the value of nicotine reinforcement threshold as a tobacco regulatory target.

The feasibility of an in-scanner smoking lapse paradigm to examine the neural correlates of lapses.

Quitting smoking is notoriously difficult. Models of nicotine dependence posit that strength of cognitive control contributes to maintaining smoking abstinence during smoking cessation attempts. We examine the role for large-scale functional brain systems associated with cognitive control in smoking lapse using a novel adaption of a well-validated behavioral paradigm. We use data from 17 daily smokers (five females) after 12 h of smoking abstinence. Participants completed up to 10 sequential 5-min functional magnetic resonance imaging (fMRI) runs, within a single scanning session. After each run, participants decided whether to stay in the scanner in order to earn additional money or to terminate the session in order to smoke a cigarette (i.e., lapse) and forego additional monetary reward. Cox regression results indicate that decreased segregation of the default mode system from the frontoparietal system undermines the ability to resist smoking. This study demonstrates the feasibility of modifying an established behavioral model of smoking lapse behavior for use in the neuro imaging environment, and it provides initial evidence that this approach yields valuable information regarding fine-grained, time-varying changes in patterns of neural activity in the moments leading up to a decision to smoke. Specifically, results lend support to the hypothesis that the time-varying interplay between large-scale functional brain systems associated with cognitive control is implicated in smoking lapse behavior.

The effects of inhaled flavors on intravenous nicotine.

Menthol is the only available flavor in combusted tobacco cigarettes; however, e-cigarettes are available in thousands of flavors. Research on flavors and rewarding properties of nicotine is limited. The present study sought to examine the acute rewarding effects of flavors inhaled from an e-cigarette, in combination with intravenous (IV) nicotine among cigarette smokers. In the present study, 24 menthol-preferring young adult (aged 18 to 30) cigarette smokers were tested under 3 different e-cigarette flavor conditions (menthol, green apple, or menthol + green apple) in a within-subject cross-over design. During each test session, each participant received 3 IV infusions (saline, 0.25 mg/70 kg nicotine, 0.5 mg/70 kg nicotine) administered 1 hr apart. The main outcome measures assessed cardiovascular, subjective, and cognitive domains. Compared with green apple or green apple + menthol, menthol produced higher ratings of "cooling" (ps < 0.01). Craving was rated higher following administration of green apple and the combined menthol + apple flavor compared to menthol alone (ps < 0.05). As expected, IV-nicotine dose-dependently increased the ratings of subjective liking/disliking and peak heart rate, improved cognitive performance, and reduced smoking urges (all ps < 0.05). These subjective, cognitive, and physiological effects of nicotine were not affected by any flavor condition. The present findings did not support an interaction between IV-nicotine dose and inhaled flavor for acute effects of nicotine. Green apple flavor, alone or in combination with menthol, could result in higher craving or insufficiently alleviate craving, relative to menthol flavor alone. Additional research is warranted to examine extended exposure to inhaled flavors on the rewarding and addictive effects of nicotine. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Naturalistic measurement of dual cue attentional bias in moderate to heavy-drinking smokers: A preliminary investigation.

INTRODUCTION: Although cigarettes and alcohol are frequently used together, few studies have evaluated evidence of attentional bias to both smoking and alcohol cues. Attentional bias (AB) is defined as preferential attention to drug-specific cues and is most often studied in a laboratory with one cue type. AB may be an important mechanism associated with cigarette and alcohol co-use. In this study, we evaluated AB to both smoking and alcohol cues in daily life using ambulatory assessment. METHODS: Daily smokers (N = 21) who consume moderate to heavy amounts of alcohol completed surveys and a dot probe task four times per day using a personal digital assistant over a period of 1 week. RESULTS: Aggregated over subjects, there was evidence of AB to smoking and AB to alcohol cues. When smoking AB was higher than the person-specific average, alcohol AB was elevated, and when alcohol AB was higher than the person-specific average, smoking AB was elevated. AB was not significantly associated with craving for cigarettes or alcohol. CONCLUSIONS: It is feasible to assess AB for cigarette and alcohol cues using ambulatory assessment. To the best of our knowledge, this is the first study to report a within-subject association between AB for two drug cues. The relationship between cigarette and alcohol use is likely dynamic and depends on context and exposure to substance-specific cues. Additionally, a larger sample may be needed to evaluate relationships between AB and craving. Further research on possible cognitive mechanisms that increase the likelihood of co-use can inform targeted interventions.

Intensive longitudinal methods for studying the role of self-regulation strategies in substance use behavior change.

PURPOSE OF REVIEW: Many psychosocial interventions for substance use disorders (SUDs) focus on teaching self-regulation strategies. Research using intensive longitudinal methods (ILM), such as ecological momentary assessment and daily diaries, is critical for elucidating if and how these strategies function as mechanisms of change among individuals with SUDs. We review this emerging area of research. RECENT FINDINGS: We found a small number of studies using ILM to study self-regulation strategies in SUD (n=18 studies), with most conducted among college student drinkers (n=9) and cigarette smokers (n=7), and few among treatment-engaged individuals, and those with other drug use disorders. There is preliminary evidence that the use of specific self-regulation strategies commonly taught in psychosocial interventions for SUDs (i.e., cognitive reappraisal, problem solving, stimulus control, harm reduction) is associated with decreased momentary or daily substance use, at the within-person level. SUMMARY: There is a need for further ILM research on self-regulation strategies as mechanisms of substance use behavior change. Such research can inform the development, refinement, and personalization of interventions that teach self-regulation strategies, including mobile interventions that facilitate strategy use in the moment. One key next step is developing psychometrically validated ILM assessments of self-regulation strategy use.

Extending the Balloon Analogue Risk Task to Assess Naturalistic Risk Taking via a Mobile Platform.

The Balloon Analogue Risk Task (BART) is a behavioral measure that is commonly used to assess risk taking propensity. The primary goal of the present study was to introduce a mobile version of the BART (mBART) that can be included within ambulatory assessment protocols to assess risk taking in daily life. Study 1 compared common BART indices (i.e., total money earned, adjusted average pumps, balloon explosions, and coefficient of variability [CV]) on a single administration of the laboratory BART on a computer and the mBART on a smartphone (n = 78). Results revealed generally consistent relationships between indices of risk taking propensity in both the laboratory BART and mBART. Study 2 administered the mBART as part of a 7-day ecological momentary assessment (EMA) protocol in a population of nondaily smokers (n = 51). Using multi-level models, results suggest that males have greater adjusted average pumps (p = .03), and that a participant's average CV is negatively related to trait sensation seeking (p = .03) and positively associated with trait positive urgency (p = .04). There were within-person effects of study day (p = .05) and environment (p = .02) with respect to adjusted average pumps such that individuals took greater risks as the study progressed and were riskier when alone compared to with others. Inclusion of the mBART in EMA did not appear to significantly increase participant burden and demonstrated acceptable levels of compliance. These results offer initial evidence supporting the feasibility and utility of the mBART for ambulatory research designs.

More to gain: dietary energy density is related to smoking status in US adults.

BACKGROUND: Given the current prevalence of both cigarette use and obesity in the United States, identification of dietary patterns that reduce mortality risk are important public health priorities. The objective of the present study was to evaluate the correlation between cigarette use and dietary energy density, a marker for diet quality, in a population of current smokers, former smokers, and never smokers. METHODS: Data from a nationally representative sample of 5293 adults who participated in the 2013-2014 National Health and Nutrition Examination Surveys (NHANES) were analyzed. Specific survey procedures were used in the analysis to account for sample weights, unequal selection probability, and clustered design when evaluating the association between dietary energy density (ED, energy per weight of food, kcal/g) and current smoking status. Never smokers reported < 100 lifetime cigarettes. Smokers were identified as individuals reporting > 100 lifetime cigarettes and current smoking status was recorded as daily, some days (nondaily), or not at all (former). RESULTS: A strong linear relationship was observed between smoking pattern and dietary ED in current smokers. Compared to never smokers, daily smokers and nondaily smokers have significantly higher dietary ED (1.79 vs. 2.02 and 1.88, respectively; both p < 0.05); demonstrating that any amount of current cigarette consumption is associated with poor diet. Though former smokers had a higher dietary ED than never smokers, this difference still significantly lower than that of current smokers (p = 0.002). CONCLUSION: These findings suggest that smoking status is associated with poor diet quality. Former smokers had a slightly lower ED value (1.84) than current non-daily smokers (1.89) but a higher value than never smokers (1.79).

Tobacco and alcohol use disorders: Evaluating multimorbidity.

There is growing interest in applying the multimorbidity model for mental health disorders - i.e. the interactive effects of co-occurring diagnoses. Alcohol use disorder (AUD) and tobacco use disorder (TUD) often occur together, but distinctive correlates of their co-occurrence have not been studied. Veterans treated by the Veterans Health Administration (VHA) nationally in FY 2012 with diagnoses of both AUD and TUD were compared to those with only AUD or only TUD on socio-environmental factors, medical and psychiatric diagnoses, and service use. Multimorbid effects were defined as those in which patients with both AUD and TUD had more serious problems greater likelihood of specific co-occurring conditions than those with either AUD alone or TUD alone. Veterans with concurrent AUD and TUD (N=153,397), as compared to those with AUD only (N=191,900) or with TUD only (N=643,377), had significantly higher rates of homelessness [odd ratios (ORs)=1.24, 1.68], hepatic disease (ORs=1.11, 2.18), substance use disorders (ORs=1.42, 3.14), receipt of a VA disability pension (ORs=1.26, 1.30) and use of substance and mental health outpatient services (ORs=1.04, 1.12). Veterans with AUD and TUD appear to have more severe problems in some, but not all, socio-environmental, medical, psychiatric, and service use domains than veterans with either of these diagnoses alone. The combination of AUD and TUD yield generally more adverse effects in diverse areas and thus reflect an emergent phenomenon that may a require a distinctive treatment approach.

Evaluating the influence of at-risk alcohol use on factors associated with smoking cessation: Combining laboratory and ecological momentary assessment.

OBJECTIVE: Most smokers want to quit but most cessation attempts end in failure. Alcohol consumption is associated with smoking behavior and relapse. We examined the associations between severity of drinking and psychological processes during a cessation attempt in the laboratory and during a quit attempt. METHODS: Smokers (N=209) enrolled in a smoking cessation study were followed from 2 weeks pre-quit through 4 weeks post-quit. Participants scoring 0-7 and 8-15 on the Alcohol Use Disorders Identification Test (AUDIT) were classified as low-risk and high-risk drinkers, respectively. Participants attended one pre-quit laboratory session before which they were required to abstain from smoking and another pre-quit session before which they smoked normally. Craving was assessed in the laboratory with the Questionnaire for Smoking Urges (QSU). A subsample of the participants also completed a 1-week ecological momentary assessment (EMA) study starting on the quit day. During EMA, craving for cigarettes was assessed, and attentional bias was assessed using a smoking Stroop task (n=119). RESULTS: High (vs. low) risk participants reported greater abstinence-induced increases in craving in the laboratory, and also exhibited greater attentional bias on the smoking Stroop task during EMA. CONCLUSIONS: High-risk drinkers exhibited a stronger increase in desire to smoke in abstinence and greater attentional bias to smoking cues early in a quit attempt, both of which may motivate continued smoking behaviors. High-risk drinkers may require more intensive or different smoking cessation interventions.

Effects of cognitive load on neural and behavioral responses to smoking-cue distractors.

Smoking cessation failures are frequently thought to reflect poor top-down regulatory control over behavior. Previous studies have suggested that smoking cues occupy limited working memory resources, an effect that may contribute to difficulty achieving abstinence. Few studies have evaluated the effects of cognitive load on the ability to actively maintain information in the face of distracting smoking cues. For the present study, we adapted an fMRI probed recall task under low and high cognitive load with three distractor conditions: control, neutral images, or smoking-related images. Consistent with a limited-resource model of cue reactivity, we predicted that the performance of daily smokers (n = 17) would be most impaired when high load was paired with smoking distractors. The results demonstrated a main effect of load, with decreased accuracy under high, as compared to low, cognitive load. Surprisingly, an interaction revealed that the effect of load was weakest in the smoking cue distractor condition. Along with this behavioral effect, we observed significantly greater activation of the right inferior frontal gyrus (rIFG) in the low-load condition than in the high-load condition for trials containing smoking cue distractors. Furthermore, load-related changes in rIFG activation partially mediated the effects of load on task accuracy in the smoking-cue distractor condition. These findings are discussed in the context of prevailing cognitive and cue reactivity theories. These results suggest that high cognitive load does not necessarily make smokers more susceptible to interference from smoking-related stimuli, and that elevated load may even have a buffering effect in the presence of smoking cues under certain conditions.

Weak ventral striatal responses to monetary outcomes predict an unwillingness to resist cigarette smoking.

As a group, cigarette smokers exhibit blunted subjective, behavioral, and neurobiological responses to nondrug incentives and rewards, relative to nonsmokers. Findings from recent studies suggest, however, that there are large individual differences in the devaluation of nondrug rewards among smokers. Moreover, this variability appears to have significant clinical implications, since reduced sensitivity to nondrug rewards is associated with poorer smoking cessation outcomes. Currently, little is known about the neurobiological mechanisms that underlie these individual differences in the responsiveness to nondrug rewards. Here, we tested the hypothesis that individual variability in reward devaluation among smokers is linked to the functioning of the striatum. Specifically, functional magnetic resonance imaging was used to examine variability in the neural response to monetary outcomes in nicotine-deprived smokers anticipating an opportunity to smoke-circumstances found to heighten the devaluation of nondrug rewards by smokers in prior work. We also investigated whether individual differences in reward-related brain activity in those expecting to have access to cigarettes were associated with the degree to which the same individuals subsequently were willing to resist smoking in order to earn additional money. Our key finding was that deprived smokers who exhibited the weakest response to rewards (i.e., monetary gains) in the ventral striatum were least willing to refrain from smoking for monetary reinforcement. These results provide evidence that outcome-related signals in the ventral striatum serve as a marker for clinically meaningful individual differences in reward-motivated behavior among nicotine-deprived smokers.

Associations between self-control and dimensions of nicotine dependence: a preliminary report.

Self-control plays an important role in several health-related behaviors, including cigarette smoking. There is some evidence that individual differences in self-control are negatively associated with overall levels of nicotine dependence but, to our knowledge, finer-grained relationships between these constructs have not been explored. This is an important knowledge gap, as nicotine dependence is thought to be composed of separate dimensions that motivate smoking behavior in relatively unique ways. The goal of this preliminary study was to begin to characterize the potentially nuanced associations between self-control and facets of nicotine dependence using data pooled from two previous studies (n=282). Specifically, we examined the correlation between self-control and the following dimensions of nicotine dependence: compulsion to smoke due to craving and desire to avoid withdrawal symptoms; preference for smoking over other reinforcers; reduced sensitivity to the effects of smoking; consistency of smoking patterns; and smoking behavior that is rigid and immutable. In line with prior research, self-control was negatively correlated with overall levels of dependence. As predicted, however, self-control was differentially associated with distinct dimensions of nicotine dependence. Specifically, self-control was negatively correlated with the compulsion to smoke due to craving and desire to avoid withdrawal symptoms but positively correlated with the consistency of smoking patterns. Given the potential conceptual and clinical importance of such effects, additional research investigating the role(s) that individual differences in self-control play in addiction to cigarettes would be useful.