Non-pharmacological Considerations in Human Research of Nicotine and Tobacco Effects: A Review.

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.

The impacts of actual and perceived nicotine administration on insula functional connectivity with the anterior cingulate cortex and nucleus accumbens.

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.

Cannabis use motives and personality risk factors.

According to the model of substance abuse of Conrod, Pihl, Stewart, and Dongier (2000), four personality factors (i.e., anxiety sensitivity [AS], introversion/hopelessness [I/H], sensation seeking [SS], and impulsivity [IMP]) are associated with elevated risk for substance use/misuse, with each personality factor being related to preference for particular drugs of abuse (e.g., AS with anxiolytics). However, cannabis use has not been consistently linked to any one of these personality factors. This may be due to the heterogeneity in cannabis use motives. The present study explored the association between these four personality risk factors and different cannabis use motives. Cannabis users completed an interview about their motives for cannabis use as well as the self-report Substance Use Risk Profile Scale (SURPS; Woicik, Conrod, Stewart, & Pihl, 2009), which measures the four personality risk factors. Results showed that AS was associated with conformity motives and I/H was associated with coping motives for cannabis use. SS was positively associated with expansion motives and IMP was associated with drug availability motives. Thus, personality risk factors in the model of Conrod et al. (2000) are associated with distinct cannabis use motives in a pattern consistent with theory.

The effects of nicotine content information on subjective and behavioural responses to nicotine-containing and denicotinized cigarettes.

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.

The effects of alcohol on responses to nicotine-containing and denicotinized cigarettes in dependent and nondaily smokers.

BACKGROUND: Alcohol consumption has been linked to increased tobacco use and craving in both dependent and nondaily smokers, yet the extent to which these relationships depend on interactions involving nicotine remains unclear. This study examined the acute effects of alcohol on the subjective and behavioral responses to nicotine-containing tobacco and denicotinized tobacco in 17 (10 male) dependent daily smokers (DDS) and 23 (11 male) nondependent nondaily smokers (NNS). METHODS: During 4 randomized double-blind sessions, participants assessed the effects of nicotine-containing tobacco or denicotinized tobacco following the administration of a moderately intoxicating dose of alcohol (mean blood alcohol concentration = 0.076 g/dl) or a placebo beverage. They could then self-administer additional puffs of the same type of cigarette sampled over a 60-minute period using a progressive ratio task. RESULTS: In NNS, alcohol significantly increased the self-administration of both nicotine-containing and denicotinized cigarettes, and no differences in self-administration were observed between the 2 types of tobacco within either beverage condition. In contrast, in DDS, alcohol was associated with decreased denicotinized tobacco self-administration relative to the placebo beverage condition as well as with increased self-administration of nicotine-containing tobacco relative to denicotinized tobacco. DDS also exhibited relatively elevated craving following the administration of a nicotine-containing cigarette in the alcohol beverage condition. CONCLUSIONS: Findings suggest that nicotine may be critical to the drinking-smoking relationship in DDS, but that nonnicotine smoking factors may be more important in NNS.

Substance use initiation: the role of simultaneous polysubstance use.

INTRODUCTION AND AIMS: Simultaneous polysubstance use (SPU) is a common phenomenon, yet little is known about its role in substance use initiation. DESIGN AND METHODS: In the present study, 226 cannabis users completed structured interviews about their substance use history. For each substance ever used, participants provided details of their age of first use, their use in the preceding 30 days and whether they co-administered any other licit or illicit substances the first time they used the substance. RESULTS: For most illicit substances [powder cocaine, crack, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA; ecstasy), heroin, opium, gamma-hydroxybutyric acid (GHB), ketamine, psilocybin (magic mushrooms), mescaline, phencyclidine (PCP), peyote and inhalants], results showed that a clear majority of participants (≥75%) reported SPU during their first-ever use of the substance. While SPU was less common on occasions of first use of alcohol, tobacco and cannabis, a high proportion of SPU on occasions of first use of 'harder' drugs could be accounted for by the co-use of alcohol, tobacco and/or cannabis. DISCUSSION AND CONCLUSIONS: Such findings raise the possibility that specific alcohol, tobacco and/or cannabis use episodes might directly contribute to the initiation of new substance use. Understanding the role of SPU on occasions of first use might help better identify risk factors for substance use progression and improve intervention efforts.

The acute effects of nicotine on the subjective and behavioural responses to denicotinized tobacco in dependent smokers.

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.

The role of nicotine content information in smokers' subjective responses to nicotine and placebo inhalers.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A further investigation of the relations of anxiety sensitivity to smoking motives.

Prior research has shown that anxiety sensitivity (AS) is associated with smoking to reduce negative affect (e.g., [Comeau, N., Stewart, S.H., & Loba, P., (2001). The relations of trait anxiety, anxiety sensitivity and sensation seeking to adolescents' motivations for alcohol, cigarette, and marijuana use. Addictive Behaviors, 26, 803-825.]). However, given limitations in the measurement of smoking motives in previous AS studies, it has yet to be definitively established that AS is specifically related to negative reinforcement smoking motives. Moreover, the overall AS construct is comprised of three lower-order components: physical, psychological, and social concerns (e.g., [Stewart, S.H., Taylor, S., & Baker, J.M., (1997). Gender differences in dimensions of anxiety sensitivity. Journal of Anxiety Disorders, 11, 179-200.]). Previous investigations generally have not examined the relative contributions of each of these three AS components to smoking for negative reinforcement motives. The present study attempted to address each of these gaps in the literature. A sample of 119 smokers attending a tobacco intervention program (see [Mullane, J.C., Stewart, S.H., Rhyno, E., Steeves, D., Watt, M., & Eisner, A., (2008). Anxiety sensitivity and difficulties with smoking cessation. In A.M. Columbus (Ed.), Advances in Psychological Research (vol. 54A, pp. 141-155). Hauppauge, NY: Nova Science Publishers.]) completed the Anxiety Sensitivity Index (ASI; [Peterson, R.A., & Reiss, S., (1992). The Anxiety Sensitivity Index manual (2nd ed.). Worthington, OH: International Diagnostic Services.]) and the Reasons For Smoking scale (RFS; [Ikard, F.F., Green, D.E., & Horn, D., (1969). A scale to differentiate between types of smoking as related to the management of affect. International Journal of the Addictions, 4, 649-659.]) at pre-treatment. In a principal components analysis (PCA) of the RFS items, stringent parallel analysis supported a two-factor solution (negative and positive reinforcement smoking motives) as opposed to the intended six factors ([Ikard, F.F., Green, D.E., & Horn, D., (1969). A scale to differentiate between types of smoking as related to the management of affect. International Journal of the Addictions, 4, 649-659.]). ASI total scores were significantly positively correlated with both RFS factors in bivariate correlational analyses. In partial correlations, the relation between the ASI and the RFS negative reinforcement factor remained significant when controlling for RFS positive reinforcement smoking motives, but the correlation of ASI with RFS positive reinforcement motives was not significant after controlling for RFS negative reinforcement motives. At the level of AS components, AS psychological concerns were related to both negative and positive reinforcement motives, while AS physical concerns were more strongly related to negative reinforcement motives. Implications for designing targeted tobacco interventions for high AS smokers are discussed.

Patterns of simultaneous polysubstance use in drug using university students.

Simultaneous polysubstance use (SPU) is a common phenomenon, yet little is known about how various substances are used with one another. In the present study 149 drug-using university students completed structured interviews about their use of various substances. For each substance ever used, participants provided details about the type, order and amount of all substances co-administered during its most recent administration. Alcohol, tobacco and cannabis were frequently co-administered with each other and with all other substances. Chi-squared tests revealed that when alcohol was used in combination with any of cannabis, psilocybin, MDMA, cocaine, amphetamine, methylphenidate (ps < 0.01) or LSD (p < 0.05) its initial use preceded the administration of the other substance. Paired samples t-tests revealed that when alcohol was used with cocaine (p < 0.01) or methylphenidate (p < 0.05) it was ingested in greater quantities than when used in their absence. Patterns of cannabis use were not systematically related to other substances administered. Finally, using one-sample t-tests, tobacco use was demonstrated to be increased relative to 'sober' smoking rates when used with alcohol, cannabis, psilocybin, MDMA, cocaine, amphetamine (ps < 0.001), LSD (p < 0.01) or methylphenidate (p < 0.05). Results suggest that many substances are routinely used in a SPU context and that the pattern in which a substance is used may be related to other substances co-administered.