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This paper evaluates the arguments put forward by Robinson and Pritchard (R&P, this volume) that the conclusions of the US Surgeon General (USDHHS 1988) that nicotine is addictive were ill founded. R&P state that nicotine does not cause intoxication, that many smokers do not exhibit compulsive use, that nicotine is not a euphoriant, that nicotine is a weak reinforcer in other species, that non-pharmacological aspects of smoking are important and that negative affect control accounts for more of the variance in questionnaire measures of smoking motives than does habit. This paper points out that intoxication and a euphoriant effect are not normally considered to be central to dependence potential, that no addictive drug results in compulsive use in all users in all situations, that animals do reliably self-administer nicotine, that evidence concerning the apparent importance of non-pharmacological components of smoking do not diminish the importance of pharmacological aspects and that 'variance accounted for' of self-report measures of smoking motivation do not bear on the issue of the importance of those motives. The paper concludes with a summary of the essence of the argument that cigarettes are addictive and that nicotine is the primary focus of that addiction. [ABSTRACT FROM AUTHOR]

Rationale: Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high, and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. Objective: The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. Results: Imaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. Conclusions: Although mGluR5 NAMs attenuate most of the key facets of nicotine dependence, they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many 'off-target' effects to be used clinically. However, newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence. [ABSTRACT FROM AUTHOR]

Rationale: The mildly euphoric and cognitive enhancing effects of nicotine play a role in the initiation of smoking, while dysphoria and anxiety associated with smoking cessation contribute to relapse. After the acute withdrawal phase, smoking cues, a few cigarettes (i.e., lapse), and stressors can cause relapse. Human and animal studies have shown that neuropeptides play a critical role in nicotine addiction. Objectives: The goal of this paper is to describe the role of neuropeptide systems in the initiation of nicotine intake, nicotine withdrawal, and the reinstatement of extinguished nicotine seeking. Results: The reviewed studies indicate that several drugs that target neuropeptide systems diminish the rewarding effects of nicotine by preventing the activation of dopaminergic systems. Other peptide-based drugs diminish the hyperactivity of brain stress systems and diminish withdrawal-associated symptom severity. Blockade of hypocretin-1 and nociceptin receptors and stimulation of galanin and neurotensin receptors diminishes the rewarding effects of nicotine. Both corticotropin-releasing factor type 1 and kappa-opioid receptor antagonists diminish dysphoria and anxiety-like behavior associated with nicotine withdrawal and inhibit stress-induced reinstatement of nicotine seeking. Furthermore, blockade of vasopressin 1b receptors diminishes dysphoria during nicotine withdrawal, and melanocortin 4 receptor blockade prevents stress-induced reinstatement of nicotine seeking. The role of neuropeptide systems in nicotine-primed and cue-induced reinstatement is largely unexplored, but there is evidence for a role of hypocretin-1 receptors in cue-induced reinstatement of nicotine seeking. Conclusion: Drugs that target neuropeptide systems might decrease the euphoric effects of smoking and improve relapse rates by diminishing withdrawal symptoms and improving stress resilience. [ABSTRACT FROM AUTHOR]

Activation of arterial blood pressure has been shown to influence higher central nervous activity. In animals, induction of sleep-like states and increases of seizure and pain thresholds in response to baroreceptor stimulation have been reported. In certain human groups, mechanical stimulation of the carotid baroreceptors also increases pain thresholds. The present paper examines the hypothesis that smokers show baroreceptor dependent antinociception as compared to non-smokers. It is speculated that one effect which rewards smoking is the nicotine induced phasic blood pressure increase which leads to baroreceptor stimulation and dampens pain perception. One hundred and twenty subjects were investigated using a recently developed mechanical baroreceptor stimulation technique and an electrical pain stimulus. The group of heavy smokers showed the predicted effect: their pain thresholds were enhanced during conditions of increased baroreceptor activity as compared to the control condition. The group of medium, light and non-smokers, however, did not show this effect. Neither blood lipid levels nor diastolic or systolic blood pressure paralleled the group differences on baroreceptor dependent antinociception. In heavy smokers, the nicotine induced phasic blood pressure increase might have baroreceptor dependent pain dampening effects, which might be among the reinforcing qualities of smoking. [ABSTRACT FROM AUTHOR]

Rationale: Growing proportions of smokers in the USA do not smoke everyday and can be referred to as light and intermittent smokers (LITS). Despite a current prevalence of LITS in the USA estimated at 25-33% of all smokers, a systematic review of the literature on this group of smokers has yet to be written., Objectives: The aim of this paper is to review and evaluate research on LITS and to identify, describe and discuss commonalities and differences between LITS and daily smokers., Methods: The primary databases used to search for publications were Pub Med (National Library of Medicine) and SCOPUS (Elsevier)., Results: LITS inhale smoke and have post-smoking blood nicotine concentrations that are broadly equivalent to those found in daily smokers. However, LITS differ from daily smokers with regard to cigarette consumption and frequency of cigarette use, sociodemographic and socioeconomic characteristics, motives, personality traits, dependence, withdrawal and craving, response to smoking-related cues, quitting perception, past-smoking status, and initiation., Conclusions: In contrast to daily smokers, LITS show few or no signs of dependence as currently defined by DSM-IV criteria, appear to exercise more self-control, seem to be less impulsive, and their smoking experience is primarily associated with positive rather than negative reinforcement. Conclusions drawn from the reviewed literature highlight the multivariate factors that must be taken into account when defining LITS and emphasize the importance of further research on this increasing fraction of smokers. The potential implications of increased LITS prevalence on smoking-related disease risks remain to be thoroughly investigated.

Rationale: Although considerable progress has been made, we do not yet fully understand the behavioral and neurobiological basis of nicotine reinforcement, and without this knowledge, treatment strategies aimed at reducing smoking remain deficient., Objectives: This review describes an original perspective on nicotine reinforcement, which arises from substantial evidence of complex interactions between nicotine and nonpharmacological stimuli. We hypothesize that nicotine reinforcement derives from at least two sources: (1) primary reinforcement, an action that requires response-dependent drug administration and is capable of conveying secondary reinforcing effects on associated stimuli, and (2) the reinforcement-enhancing effect of nicotine, which directly enhances behavior maintained by salient nonnicotine stimuli and does not require a contingent relationship between drug administration and reinforced operant responding. Although novel for nicotine, this hypothesis has origins in an extensive literature on the reinforcing effects of psychostimulants. Empirical support for this hypothesis, based largely on animal models of reinforcement, will be presented., Conclusions: Animal models of drug reinforcement have evolved to reflect our growing awareness of the multidimensional nature of drug dependence in humans. Investigating the interaction between nicotine and nonpharmacological stimuli within the context of the drug self-administration paradigm in rats has generated new insights into the paradox of how nicotine, an apparently weak primary reinforcer, can sustain the robust behavior observed in self-administration and in smoking. The hypothesis presented in this paper--that nicotine acts as both a primary reinforcer and an enhancer of other nonnicotine reinforcers--provides important direction for future investigations into the neurobiology of nicotine reinforcement and treatments for smoking cessation.

Rationale: Two seemingly contrary theories describe the learning mechanisms that mediate human addictive behaviour. According to the classical incentive theories of addiction, addictive behaviour is motivated by a Pavlovian conditioned appetitive emotional response elicited by drug-paired stimuli. Expectancy theory, on the other hand, argues that addictive behaviour is mediated by an expectancy of the drug imparted by cognitive knowledge of the Pavlovian (predictive) contingency between stimuli (S+) and the drug and of the instrumental (causal) contingency between instrumental behaviour and the drug., Aims and Method: The present paper reviewed human-nicotine-conditioning studies to assess the role of appetitive emotional conditioning and explicit contingency knowledge in mediating addictive behaviour., Results: The studies reviewed here provided evidence for both the emotional conditioning and the expectancy accounts. The first source of evidence is that nicotine-paired S+ elicit an appetitive emotional conditioned response (CR), albeit only in participants who expect nicotine. Furthermore, the magnitude of this emotional state is modulated by nicotine deprivation/satiation. However, the causal status of the emotional response in driving other forms of conditioned behaviour remains undemonstrated. The second source of evidence is that other nicotine CRs, including physiological responses, self-administration, attentional bias and subjective craving, are also dependent on participants possessing explicit knowledge of the Pavlovian contingencies arranged in the experiment. In addition, several of the nicotine CRs can be brought about or modified by instructed contingency knowledge, demonstrating the causal status of this knowledge., Conclusions: Collectively, these data suggest that human nicotine conditioned effects are mediated by an explicit expectancy of the drug coupled with an appetitive emotional response that reflects the positive biological value of the drug. The implication of this conclusion is that treatments designed to modify the expected value of the drug may prove effective.

Rationale: The mood and physical symptoms scale (MPSS) was developed in the early 1980s to assess cigarette withdrawal symptoms, and variants of it have been used for 20 years. To date, no paper has been published on the properties of the scale. Objectives: To evaluate psychometric properties of MPSS and the interrelationship between the key tobacco withdrawal symptoms. Methods: The core elements of the MPSS involve 5-point ratings of depressed mood, irritability, restlessness, difficulty concentrating and hunger and 6- point ratings of strength of urges to smoke and time spent with these urges. The data set chosen for analysis was well suited to the task in that it involved a relatively large sample, abstinence was defined as "not a puff" for 24 h biochemically verified, participants were not using any medication that would have reduced withdrawal discomfort (e.g. nicotine patch), the abstinence rate was very high resulting in minimal bias due to attrition, and ratings were provided on three occasions prior to abstinence. The study involved 111 smokers setting a target quit date of whom 106 attempted abstinence and 96 achieved it. Results: The MPSS items were stable prior to abstinence and sensitive to abstinence. Post-abstinence increases in mood and physical symptoms demonstrated a high level of internal coherence. Ratings of urges to smoke correlated highly with changes in mood and other symptoms. Ratings of hunger correlated less well with the scale as a whole and may involve some distinct processes. Conclusions: The MPSS meets the key requirements of a cigarette withdrawal scale. Although urge to smoke/craving was not included in the list of DSM-IV withdrawal symptoms, should be regarded as forming part of the withdrawal syndrome. [ABSTRACT FROM AUTHOR]

This paper reports on a double blind trial of the effect of buspirone, 15 mg per day, on cigarette withdrawal symptoms and ability of smokers to maintain abstinence during treatment. A total of 61 smokers were randomly assigned to active or placebo conditions. They were maintained on their drug for 2 weeks prior to attempting abstinence and then for a further 4 weeks of abstinence. Subjects attended weekly group sessions of a psychological treatment programme. There was no evidence that the side effects in the active drug group were worse than those in the placebo group. Although there was no significant difference between active and placebo conditions on withdrawal symptoms, smokers in the active drug condition were more than twice as likely to maintain abstinence for the duration of the study than those in the placebo condition (47% versus 16%, chi square = 5.3, P less than 0.025). The results provide preliminary evidence for short-term efficacy of buspirone as an aid to smoking cessation at a low dose. They also provide evidence of a dissociation between withdrawal symptoms and successful abstinence.

This paper describes the results of a postmortem study of the effects of tobacco smoking on the concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) as well as the binding of [3H]-8-hydroxy-(di-n-propylamino)-tetralin ([3H]-8-OH-DPAT) and [3H]-ketanserin in six discrete regions of human brain. Smoking was associated with significant decreases in the concentrations of 5-HIAA in the hippocampal neocortex (P less than 0.001), hippocampal formation (P less than 0.05) and the median raphe nuclei (P less than 0.05). The 5-HT level of the hippocampal formation was also significantly reduced in smokers (P less than 0.05). These changes were accompanied by significant increases in the binding of [3H]-8-OH-DPAT in the hippocampal neocortex (P less than 0.01) and hippocampal formation (P less than 0.05). [3H]-Ketanserin binding in the brain regions studied was unaffected by smoking. It is concluded that smoking is associated with a regionally selective decrease in the activity of the serotonergic system of the human hippocampus.

Rationale: Tobacco harm reduction (THR) involves encouraging adult smokers who would otherwise continue to smoke to transition to less harmful forms of nicotine delivery. These products must offer adult smokers reduced exposure to chemicals associated with tobacco combustion, satisfactory blood plasma nicotine levels and serve as an acceptable alternative. The most recent THR innovation is tobacco-free oral nicotine pouches. Objectives: This study aimed to compare pharmacokinetic, pharmacodynamic and safety and tolerability profiles of two nicotine pouch variants (ZoneX #2 (5.8 mg nicotine/pouch); ZoneX #3 (10.1 mg nicotine/pouch)) with cigarette to assess the pouches' THR potential. Methods: This was a controlled use, randomised, open-label, cross-over clinical study with 24 healthy adult traditional tobacco users. Pharmacokinetic (plasma nicotine levels; up to 8 h post-use), pharmacodynamic (urge to smoke, product liking; up to 4 h post-use) and short-term safety and tolerability profiles were assessed. Results: Distinct nicotine pouch pharmacokinetic profiles indicated nicotine absorption via the oral mucosa. Plasma nicotine levels were lower, and time to peak slower, for the nicotine pouches compared to cigarette (Cmax cigarette: 11.6 ng/ml vs. #2: 5.2 ng/ml, p < 0.0001; #3: 7.9 ng/ml, p < 0.0003) (Tmax cigarette: 8.6 min vs. #2: 26 min; #3: 22 min). All products effectively reduced subjects' urge to smoke and presented favourable product liking scores; nicotine pouches were also well tolerated following short-term use (no serious adverse events). Conclusions: Overall, the assessed ZoneX nicotine pouches may offer an acceptable alternative for adult smokers to achieve satisfactory levels of nicotine delivery and, based on the pharmacokinetic parameters and under the study conditions, likely have a lower abuse liability and addictive potential for current adult smokers compared to continued cigarette smoking. Clinical trial identifier: NCT04891406 (clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Rationale: Drug addiction may be characterised by a hypersensitivity to drug rewards and a hyposensitivity to non-drug rewards. This imbalance may become further polarised during acute abstinence. Objectives: (i) Examine the differences between dependent and occasional smokers in choices for, motivation for and self-reported wanting and liking of cigarette and non-drug rewards. (ii) Examine the effects of 12-h nicotine abstinence on these metrics. Methods: Dependent ( n = 20) and occasional, non-dependent smokers ( n = 20) were tested after ad libitum smoking and ≥12-h of nicotine abstinence. A novel task was developed (Drug, Reward and Motivation-Choice (DReaM-Choice)) in which different rewards (cigarettes, music and chocolate) could be won. In each trial, participants chose between two rewards and then could earn the chosen reward via repeated button-pressing. Participants subsequently 'consumed' and rated subjective liking of the rewards they had won. Results: Compared with occasional smokers, dependent smokers made more choices for ( p < 0.001), pressed more for ( p = 0.046) and reported more wanting ( p = 0.007) and liking ( p < 0.001) of cigarettes, and also made fewer choices for chocolate ( p = 0.005). There were no differences between the groups on button-pressing for chocolate or music. However, the balance between drug and non-drug reward processing was different between the groups across all metrics. Twelve-hour nicotine abstinence led to more cigarette choices ( p < 0.001) and fewer music choices ( p = 0.042) in both groups. Conclusions: Nicotine dependence was associated with a hypersensitivity to cigarette rewards, but we found little evidence indicating a hyposensitivity to non-drug rewards. Our findings question the moderating influence of dependence on how acute nicotine abstinence affects reward processing. [ABSTRACT FROM AUTHOR]

Objective: Stimulant use instigates abstinence syndrome in humans. miRNAs are a critical component for the pathophysiology of stimulant abstinence. Here we sought to identify a miRNA marker of methamphetamine abstinence in the circulating extracellular vesicles (cEVs). Methods: miR-137 in the cEVs was quantified by qPCR in thirty-seven patients under methamphetamine abstinence and thirty-five age-matched healthy controls recruited from 2014 to 2016 from the general adult population in a hospital setting, Seoul, South Korea. Diagnostic power was evaluated by area under curve in the receiver-operating characteristics curve and other multiple statistical parameters. Results: Patients under methamphetamine abstinence exhibited a significant reduction in cEV miR-137. Overall, cEV miR-137 had high potential as a blood-based marker of methamphetamine abstinence. cEV miR-137 retained the diagnostic power irrespective of the duration of methamphetamine abstinence or methamphetamine use. Interestingly, cEV miR-137 interacted with age: Control participants displayed an aging-dependent reduction of cEV miR-137, while methamphetamine-abstinent patients showed an aging-dependent increase in cEV miR-137. Accordingly, cEV miR-137 had variable diagnostic power depending on age, in which cEV miR-137 more effectively discriminated methamphetamine abstinence in the younger population. Duration of methamphetamine use or abstinence, cigarette smoking status, depressive disorder, or antidepressant treatment did not interact with the methamphetamine abstinence-induced reduction of cEV miR-137. Conclusion: Our data collectively demonstrated that miR-137 in the circulating extracellular vesicles held high potential as a stable and accurate diagnostic marker of methamphetamine abstinence syndrome. [ABSTRACT FROM AUTHOR]

Rationale: Reinforcer pathology (RP) is a theoretical model based on two processes: delay discounting (DD) and drug demand. Given that RP has been shown to have a predictive value on smoking behaviors, several studies have explored which interventions can reduce RP. Consistent with the RP framework, episodic future thinking (EFT) has shown effects on treatment outcomes and RP processes. The vast majority of studies that assess the effects of EFT on RP consist of experimental studies, and no previous research has tested these effects in a clinical sample of smokers. Objectives: The primary aim of this study was to assess the effects of EFT on RP throughout the course of a smoking cessation intervention in smokers with substance use disorders (SUDs). Methods: Participants were randomized to cognitive behavior therapy (CBT) + EFT (n = 39) or CBT + EFT + contingency management (n = 33). Cotinine, frequency of EFT practices, cigarette purchase task (CPT), and DD were evaluated in treatment sessions. Mixed-effects model repeated measures analysis was used to explore DD and CPT in-treatment changes as a function of EFT practices and cotinine levels. Results: Greater practice of the EFT component significantly reduced cigarette demand (p <.020) as well as DD (p =.003). Additionally, a greater reduction in cotinine levels coupled with greater EFT practice led to a greater decrease in cigarette demand (p <.014). Conclusions: EFT reduced the two facets of RP in treatment-seeking smokers with SUDs. [ABSTRACT FROM AUTHOR]

In the present pilot study, an attempt was made to shape and maintain cigarette smoking behavior in rhesus monkeys both with and without the simultaneous use of other reinforcers. Initially, 14 monkeys were trained to suck air and puff on cigarettes using sweetened liquid reinforcer. After smoking had been established, the sweetened liquid reinforcement was removed. Smoking without this reinforcement, referred to as 'voluntary smoking,' was then observed during 20-h daily sessions. Of 14 monkeys studied, 2 have engaged in voluntary smoking for 2 years or longer. The maximum figures recorded for any single 20-h session were 3,271 puffs (20 cigarettes) in one monkey and 16,384 puffs (47 cigarettes) in the other. Although the baseline variability of smoking by these monkeys was quite high, low-nicotine and nicotine-free cigarettes seemed to lead to clear decreases in smoking. In 2 other monkeys that did not perform voluntary smoking, smoking was reestablished under a random-time or a tandem schedule for sweetened liquid reinforcement. Within this situation ('schedule-controlled smoking') schedule manipulations also led to changes in intake of cigarette smoke. The voluntary smoking model described in the present paper should be useful for studying the factors involved in initiating and maintaining smoking behavior and for studying the psychopharmacological effects of smoking, while the schedule-controlled smoking model should be useful for studying the physiological effects of smoking and for studying th relationship of smoking with various disease entities.

Background: Cue-reactivity is the array of responses that smokers exhibit when exposed to conditioned and contextual stimuli previously associated to substance use. The difficulty to experimentally recreate the complexity of smokers' spatial experience and context requires more ecological models. Virtual reality (VR) creates a state of immersion close to reality allowing controlled assessments of behavioral responses. To date, no studies investigated brain activation associated to smoking cue-reactivity in VR using electroencephalography (EEG). Aims: To investigate whether a VR cue-reactivity paradigm (a) may increase smoking craving, (b) is feasible with EEG recording, and (c) induces craving levels associated to EEG desynchronization. Methods: Smokers (N = 20) and non-smokers (N = 20) were exposed to neutral and smoking-related VR scenarios, without and with smoking conditioned stimuli, respectively. EEG was recorded from occipital and parietal leads throughout the sessions to assess alpha band desynchronization. Smoking and food craving and presence visual analogue scales (VAS) were assessed during the session. Results: To be smoker, but not non-smoker, significantly influenced smoking craving VAS induced by smoking cue VR but not by neutral VR. No significant food craving changes was observed during the VR sessions. The new finding was that EEG alpha band power in posterior leads was significantly increased by the smoking context scenario only in smokers, and that the degree of smoking (i.e., heavy vs. light) was significantly associated to this neurophysiological measure. Conclusions: This study demonstrated, for the first time, the feasibility of EEG recording in a VR setting, suggesting that EEG desynchronization may be a neurophysiological marker of smoking cue-reactivity. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that patients with schizophrenia have higher smoking rates and worse cognitive function than healthy controls. However, there is no consistent conclusion about the relationship between smoking and cognitive impairment. Objectives: The main purpose of this study was to explore the effects of smoking on cognitive function by using MATRICS Cognitive Consensus Battery (MCCB) in Chinese male patients with schizophrenia. Methods: There were 164 patients with chronic schizophrenia and 82 healthy controls. All subjects were interviewed about smoking status. The cognitive function was assessed by MCCB and Stroop tests. The Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptoms of the patients. Results: Compared with healthy controls, patients had lower MCCB scores in all of its domain scores (all p < 0.05). In the patients, the scores of spatial span test (42.3 ± 11.6), digital sequence test (42.9 ± 10.6), and Hopkins Verbal Learning Test (42.2 ± 10.1) were lower in smokers than those in nonsmokers (all p < 0.05, effect size: 0.28–0.45). Logistic regression analysis showed that the smoking status of the patients was correlated with digital sequence score (p < 0.05, OR = 1.072, 95%CI: 1.013–1.134). Multivariate regression analysis showed that the spatial span total score (β = − 0.26, t = − 2.74, p < 0.001) was associated with the duration of smoking in patients with schizophrenia. Conclusions: Our findings show that smoking patients with chronic schizophrenia exhibit more severe cognitive impairment than nonsmoking patients, especially in working memory and executive function. [ABSTRACT FROM AUTHOR]

Rationale: Little is known about relapse among non-daily, intermittent smokers (ITS), who have difficulty quitting, despite a lack of dependence. Objectives: To analyze situations associated with temptations to smoke and smoking lapses among ITS trying to maintain abstinence. Methods: Participants were 130 initially abstinent ITS in the placebo arm of a smoking cessation study. EMA data captured participants' situations and states in temptations (n = 976), including those that eventuated in lapses (n = 147), for up to 6 weeks. Randomly timed assessments assessed background states (n = 11,446). Participants also reported coping performed to prevent lapses. Multilevel analyses compared temptations to background situations, and lapse episodes to resolved temptations. Results: Temptations were marked by exposure to smoking cues, including others smoking, lax smoking restrictions, and alcohol consumption, as well as more negative affect. Lapses did not differ from resolved temptations in craving intensity, but were more often associated with smoking cues and availability of cigarettes, alcohol consumption, and worse affect, and were more often attributed to good moods. Both behavioral and cognitive coping responses were associated with avoiding lapsing, but behavioral coping had much larger effects. The effects of affective distress on lapse risk were mediated by its effects on coping. Conclusions: Smoking cues play a major role in ITS' temptations and lapses, perhaps indicating a degree of behavioral dependence. Affective distress also played a role in ITS lapses, undermining the idea that the affective distress seen in daily smokers' lapses is due to nicotine withdrawal. The data reinforce the important role of coping in preventing lapses. [ABSTRACT FROM AUTHOR]

Rationale: The smallest difference in nicotine that can change a smoker's cigarette preference is not clearly known. Objective: A procedure to efficiently identify the difference in nicotine needed to change cigarette preference could help inform research to gauge effects of a nicotine reduction policy. Methods: Using a within-subject design, we assessed preference for research cigarettes varying in nicotine contents (NIC; 18.7, 10.8, 5.3, 2.3, and 1.3 mg/g of tobacco), relative to a very low nicotine cigarette (VLNC; 0.4 mg/g), in 17 adult-dependent non-menthol smokers abstinent overnight. Only one NIC was compared vs. the VLNC per session, with order of the five NIC contents randomized across sessions on five separate days. Preference for each NIC vs. VLNC was determined by validated forced choice procedure, with those NIC chosen more than VLNC indicating greater reinforcement due to greater nicotine per se. Secondarily, less preference for lower NIC (vs. VLNC), relative to choice for the highest NIC, 18.7 mg/g (vs. VLNC), indexed reduced reinforcement. Results: Overall, NIC choices increased as their nicotine increased, as anticipated. Relative to the 0.4 mg/g VLNC, choice was greater for NIC ≥ 5.3 mg/g but not ≤ 2.3 mg/g. Correspondingly, relative to choice for 18.7 mg/g, choice was less for NIC ≤ 2.3 mg/g but not ≥ 5.3 mg/g. Conclusions: Although replication with larger samples and longer access is needed, results indicate that nicotine reduction to ≤ 2.3 mg/g in cigarettes would attenuate reinforcement. This choice procedure may efficiently inform future clinical trials to assess relative reinforcing effects of smoking reduced nicotine cigarettes. [ABSTRACT FROM AUTHOR]

Rationale: About 1.1 billion people smoke tobacco globally and tobacco-related health care costs 1.8% of GDP in many countries. The majority of people are unable to quit smoking despite pharmacological intervention, highlighting the need to understand the pathophysiology associated with tobacco smoking to aid the development of new therapeutics. The reinforcing effects of tobacco smoking are thought to be mediated by the dopamine system. However, the nature of dopamine dysfunction seen in smokers is unclear. Objective: To determine the nature and robustness of the evidence for dopaminergic alterations in smokers. Methods: The entire MEDLINE, EMBASE, and PsycINFO databases were searched for studies from inception date to November 18, 2018. In vivo human molecular imaging studies of dopamine measures (dopamine synthesis or release capacity, transporter levels, receptor levels) in tobacco smokers were selected. Demographic, clinical, and imaging measures were extracted from each study and meta-analyses, and sensitivity analyses were conducted. Results: Fourteen studies met inclusion criteria comprising a total sample of 219 tobacco smokers and 297 controls. The meta-analysis showed a significant reduction in dopamine transporter availability in the smokers relative to controls with an effect size of − 0.72 ([95% CI, − 1.38 to − 0.05], p = 0.03). However, there was no difference in D2/3 receptor availability in smokers relative to controls (d = −0.16 ([95% CI, − 0.42 to 0.1], p = 0.23). There were insufficient studies for meta-analysis of other measures. However, findings from the published studies indicated blunted dopamine release and lower D1 receptor availability, while findings for dopamine synthesis capacity were inconsistent. Conclusion: Our data indicate that striatal dopamine transporter availability is lower but D2/3 receptors are unaltered in smokers relative to controls. We discuss the putative mechanisms underlying this and their implications. [ABSTRACT FROM AUTHOR]

Rationale: The Food and Drug Administration is considering severely restricting the nicotine in cigarettes, to reduce smoking. A study showed that non-daily, intermittent smokers (ITS) randomized to very-low-nicotine-content cigarettes (VLNCCs) reduced their cigarette consumption.Objectives: To assess whether increased smoking intensity of VLNCCs compensated for some of the reduced cigarette consumption.Methods: After a 2-week baseline smoking their own-brand cigarettes, 118 ITS were randomized to VLNCCs (~ 1 mg nicotine/g tobacco), and 120 to normal-nicotine-content cigarettes (NNCCs; ~ 16 mg/g) for 10 weeks. Laboratory measures of smoking intensity—total puff volume and carbon monoxide (CO) boost—assessed single cigarettes smoked in up to three laboratory topography sessions. Field measures assessed returned cigarette butts, averaged over up to five 2-week intervals: the mass of tobacco burned (computed from residual mass of butts) and the intensity of smoking (by scanning of returned filters). Analysis was by mixed model random effects models using baseline values as covariates.Results: ITS in the VLNCC group puffed less smoke in topography sessions (−38.50 mL [−75.21, −1.78]; p < 0.04), but showed no difference in CO boost. Participants in the VLNCC group burned 0.02 [0.04, 0.002] grams less tobacco per cigarette (p < 0.03). Analysis of filters showed their smoking intensity declined over time, compared to NNCC participants (p < 0.04). “Cheating” by smoking normal cigarettes did not moderate these effects.Conclusions: ITS did not increase their smoking intensity when switched to VLNCCs; indeed, their smoking intensity decreased. Reductions in cigarette consumption seen when ITS are switched to VLNCCs were not compensated by increased smoking intensity. [ABSTRACT FROM AUTHOR]

Rationale: Cigarette smokers often experience cognitive decrements during abstinence from tobacco, and these decrements may have clinical relevance in the context of smoking cessation interventions. However, limitations of the behavioral summary statistics used to measure cognitive effects of abstinence, response times (RT) and accuracy rates, may restrict the field’s ability to identify robust abstinence effects on task performance and test mechanistic hypotheses about the etiology of these cognitive changes.Objectives: The current study explored whether a measurement approach based on mathematical models of cognition, which make the cognitive mechanisms necessary to perform choice RT tasks explicit, would be able to address these limitations.Methods: The linear ballistic accumulator model (LBA: Brown and Heathcote, Cogn Psychol 57(3):153-178, 2008) was fit to an existing data set from a study that evaluated the impact of overnight abstinence on flanker task performance.Results: The model-based analysis provided evidence that smokers’ rates of mind wandering increased during abstinence, and was able to index this effect while controlling for participants’ strategy changes that were related to the specific experimental paradigm used.Conclusion: Mind wandering is a putative explanation for cognitive withdrawal symptoms during smoking cessation and may be indexed using the LBA. More broadly, the use of formal model-based analyses in future research on this topic has the potential to allow for strong and specific tests of mechanistic explanations for these symptoms. [ABSTRACT FROM AUTHOR]

Rationale: We previously reported that following a short-term product use period, use of non-menthol Vuse Solo electronic cigarettes (ECs) resulted in product effect-related subjective responses and nicotine uptake between those of combustible cigarettes (high-abuse liability comparator) and nicotine gum (low-abuse liability comparator); the results were generally closer to those of nicotine gum.Objective: Using a similar design to the previous study, we evaluated the abuse liability of three menthol-flavored Vuse Solo ECs with the same nicotine contents (14, 29, and 36 mg) in a group of EC-naïve, menthol cigarette smokers, relative to comparator products.Methods: Six-hour nicotine uptake and ratings of subjective effects were used to determine abuse liability and pharmacokinetics.Results: Use of menthol Vuse Solo resulted in significantly lower responses to subjective measurements (product liking, intent to use product again, and liking of positive product effects), higher urge to smoke responses, and a lower peak (Cmax) and overall extent (AUC0-360) of nicotine uptake compared to smoking the usual brand menthol cigarette. When compared with use of nicotine gum, subjective responses to use of menthol Vuse ECs were in the same direction as those resulting from smoking cigarettes but were more similar to nicotine gum use in magnitude than they were to cigarettes.Conclusion: These findings are concordant with our previous results and provide evidence that menthol Vuse Solo ECs have abuse liability that is lower than menthol cigarettes and potentially greater than that of nicotine gum.Trial registration: ClinicalTrials.gov identifier: NCT02664012 [ABSTRACT FROM AUTHOR]

Rationale: Current research on factors that predict smoking lapse behavior is limited in its ability to fully characterize the critical moments leading up to decisions to smoke.Objectives: We used a validated and widely used experimental analogue for smoking lapse to assess how moment-to-moment dynamics of craving relate to decisions to smoke.Methods: Heavy smokers (N = 128, M age = 35.9) participated in a 50-min laboratory delay to smoking task on 2 consecutive days, earning money for each 5 min they remained abstinent or ending the task by choosing to smoke. Participants rated craving and negative affect levels immediately prior to each choice. Participants were randomized to smoking as usual (n = 50) or overnight abstinence (n = 50 successfully abstained, n = 22 failed abstaining) prior to session 2. Discrete-time hazard models were used to examine craving and negative affect as time-varying predictors of smoking.Results: Higher craving levels prior to smoking opportunities predicted increased risk of smoking. When controlling for craving levels, incremental increases in craving predicted increased smoking risk. Increases in negative affect incrementally predicted increased smoking risk at session 2 only. Smokers who failed to abstain were at a higher risk of smoking than those who successfully abstained, whereas abstinent and non-abstinent smokers did not differ in smoking risk.Conclusions: Findings demonstrate an extension of the smoking lapse paradigm that can be utilized to capture momentary changes in craving that predict smoking behavior. Evaluations of nuanced craving experiences may inform clinical and pharmacological research on preventing smoking lapse and relapse. [ABSTRACT FROM AUTHOR]

Background: Despite evidence supporting the benefits of cannabinoids for symptom control across a wide range of medical conditions, concerns have been raised regarding the potential misuse and/or problematic use of cannabinoids (CBs).Objective: The first objective of this study was to examine the incidence of problematic prescription cannabinoid use (PPCBU) over a 12-month period among patients initiating cannabinoid therapy. The second objective was to examine the factors associated with PPCBU. A total of 265 patients who were prescribed oral cannabinoid therapy as part of usual medical practice were enrolled into this prospective observational study. Patients first completed a series of baseline questionnaires assessing demographic, clinical, and substance use variables. Three measures designed to assess PPCBU were then administered at 3, 6, and 12 months after initiation of cannabinoid therapy.Results: At each of the follow-up assessment time points, a significantly greater number of patients scored below (vs above) cutoff scores on the three main PPCBU outcomes (all p’s < .001). At any follow-up time point, a maximum of roughly 25% of patients demonstrated PPCBU. Heightened odds of PPCBU were observed among patients with a history of psychiatric problems, tobacco smokers, and recreational cannabis users (all p’s < .05). Results indicated that past-year substance abuse, assessed using the DAST-20, was the strongest predictor of PPCBU (p < .005).Conclusion: Findings from the present study could have implications for clinicians considering the use of cannabinoids for the management of patients with medical conditions. Although results indicated that the majority of patients included in this study did not reach cutoff scores on the three main PPCBU outcomes, our findings suggest that PPCBU should be routinely assessed and monitored over the course of cannabinoid therapy, particularly among patients with a history of psychiatric or substance use problems. [ABSTRACT FROM AUTHOR]

Rationale: It is presently unclear whether diabetic rats experience greater rewarding effects of nicotine and/or negative affective states produced by nicotine withdrawal. Objective: The present study utilized a rodent model of diabetes to examine the rewarding effects of nicotine and negative affective states and physical signs produced by withdrawal. Methods: Separate groups of rats received systemic administration of either vehicle or streptozotocin (STZ), which destroys insulin-producing beta cells in the pancreas and elevates glucose levels. Place conditioning procedures were utilized to compare the rewarding effects of nicotine (conditioned place preference; CPP) and negative affective states produced by withdrawal (conditioned place aversion; CPA) in vehicle- and STZ-treated rats. CPA and physical signs of withdrawal were compared after administration of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal in nicotine-dependent rats. A subsequent study utilized elevated plus maze (EPM) procedures to compare anxiety-like behavior produced by nicotine withdrawal in vehicle- and STZ-treated rats. Results: STZ-treated rats displayed greater rewarding effects of nicotine and a larger magnitude of aversive effects and physical signs produced by withdrawal as compared to vehicle-treated controls. STZ-treated rats also displayed higher levels of anxiety-like behavior on the EPM during nicotine withdrawal as compared to controls. Conclusion: The finding that both nicotine reward and withdrawal are enhanced in a rodent model of diabetes implies that the strong behavioral effects of nicotine promote tobacco use in persons with metabolic disorders, such as diabetes. [ABSTRACT FROM AUTHOR]

Rationale: Some individuals are particularly responsive to reward-associated stimuli ('cues'), including the effects of these cues on craving and relapse to drug-seeking behavior. In the cases of nicotine and alcohol, cues may acquire these abilities via the incentive-enhancing properties of the drug. Objectives: To determine the interaction between cue-responsivity and nicotine reinforcement, we studied the patterns of nicotine self-administration in rats categorized based on their tendency to approach a food-predictive cue ('sign-trackers') or a reward-delivery location ('goal-trackers'). In a second experiment, we determined whether nicotine and ethanol altered the incentive value of a food cue. Methods: Rats were classified as sign- or goal-trackers during a Pavlovian conditioned approach paradigm. Rats then self-administered intravenous nicotine (0.03 mg/kg infusions) followed by extinction and cue-induced reinstatement tests. We also tested the effects of nicotine (0.4 mg/kg base s.c.) or ethanol (0.7 g/kg i.p.) on the approach to, and reinforcing efficacy of, a food cue. Results: Sign-trackers showed greater reinstatement in response to a nicotine cue. Further, nicotine enhanced sign-tracking but not goal-tracking to a food cue and also enhanced responding for the food cue during the conditioned reinforcement test. Conversely, ethanol reduced sign-tracking and increased goal-tracking, but had no effect on conditioned reinforcement. Conclusions: Our studies demonstrate that the tendency to attribute incentive value to a food cue predicts enhanced cue-induced reinstatement. Additionally, the incentive value of food cues is differentially modulated by nicotine and ethanol, which may be related to the reinforcing effects of these drugs. [ABSTRACT FROM AUTHOR]