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 impact of cannabidiol placebo on responses to an acute stressor: A replication and proof of concept study.

BACKGROUND: Our group has previously reported that cannabidiol (CBD) expectancy alone blunts markers of stress, particularly during anticipation, but it is not clear the extent to which such findings were specific to the methods utilized. AIMS: To examine CBD-related placebo effects on stress reactivity and anticipation and to validate a protocol to be used in a neuroimaging study. METHODS: Forty-eight healthy adults (24 female) were randomly assigned to be informed that they ingested a CBD-containing oil or a CBD-free oil despite receiving the same oil (CBD-free). Following oil administration, participants engaged in a laboratory stressor and were then incorrectly informed that they would engage in a second more difficult task following a waiting period. Subjective state (sedation, energy, stress, anxiety) and heart rate were assessed at baseline, post-oil administration, immediately following the first stressor, and while anticipating the second stressor. RESULTS: Subjective stress and anxiety were significantly elevated immediately following the stressor (p-values < 0.001). CBD expectancy was associated with increased subjective sedation (p < 0.01) and tended to be associated with blunted subjective stress (p = 0.053). Post hoc within-condition pairwise compassions suggested a return to pre-stressor levels during the anticipation period in the CBD condition for subjective stress and anxiety (p = 0.784, 0.845), but not the CBD-free condition (p = 0.025, 0.045). CONCLUSION: Results replicate and extend previous findings that CBD expectancy alone can impact stress- and anxiety-relevant responses in the laboratory context.

The impact of cannabidiol placebo on amygdala-based neural responses to an acute stressor.

BACKGROUND: Cannabidiol (CBD) impacts brain regions implicated in anxiety reactivity and stress reactivity (e.g., amygdala, anterior cingulate cortex (ACC), anterior insula (AI)); however, placebo-controlled studies are mixed regarding CBD's anxiolytic effects. We previously reported that CBD expectancy alone can alter subjective, physiological, and endocrine markers of stress/anxiety; however, it is unclear whether these findings reflect altered brain reactivity. This study evaluated whether CBD expectancy independently alters amygdala resting-state functional connectivity (rsFC) with the ACC and AI following acute stress. METHOD: Thirty-eight (20 females) healthy adults were randomly assigned to receive accurate or inaccurate information regarding the CBD content of a CBD-free oil administered during a single experimental session. Following a baseline resting state MRI scan, participants administered their assigned oil sublingually, engaged in a stress task (serial subtraction with negative feedback) inside the scanner, and underwent another resting state MRI scan. Amygdala rsFC with the ACC and AI was measured during each scan, and the subjective state was assessed at six time points. Outcomes were analyzed using ANCOVA. RESULTS: CBD expectancy (vs CBD-free expectancy) was associated with significantly weaker rsFC between the left amygdala and right ACC (p = 0.042), but did not systematically alter amygdala-AI rsFC (p-values > 0.05). We also replicated our previously reported CBD expectancy effects on subjective stress/anxiety in the scanner context. CONCLUSION: CBD placebo effects may be sufficient to alter neural responses relevant to its purported anxiolytic and stress-relieving properties. Future work is needed to replicate these results and determine whether CBD expectancy and pharmacology interact to alter neural anxiety reactivity and stress reactivity.

Dual users' perceptions of the addictive properties of cigarettes versus E-cigarettes.

INTRODUCTION: Electronic cigarettes ("e-cigarettes") are commonly promoted as a less-harmful alternative to combustible cigarettes, yet many individuals concurrently use both products ("dual users"). Little is known about the extent to which dual users' perceptions of the addictive properties of these products differ, or to what extent there are differences in the factors that elicit craving for each product. METHODS: An online survey evaluated beliefs about the addictive properties of cigarettes vs e-cigarettes and the situational and affective precipitants of product craving, on a scale from 1 to 10, in a sample of Canadian adults that reported past-month use of combustible and e-cigarettes (N = 175; 79 female). RESULTS: Participants rated cigarettes as more addictive than e-cigarettes, and on average reported higher levels of dependence on combustible cigarettes. While the addictive properties of both combustible and e-cigarettes were largely attributed to nicotine, non-nicotine factors (e.g. flavouring, other non-nicotine ingredients) were believed to make a relatively stronger contribution to the addictive properties of e-cigarettes, particularly among women. Participants reported greater increases in craving for combustible cigarettes in response to negative affective states and situational factors, and these effects were strongest among participants that displayed greater dependence on combustible tobacco relative to e-cigarettes. CONCLUSIONS: Dual users perceived cigarettes to be more addictive than e-cigarettes and attributed the addictive properties of each product to different factors. Further, cravings for combustible cigarettes were more strongly linked to certain negative affective states and situational factors relative to e-cigarettes. Findings suggest that there may be limited substitutability between combustible and e-cigarettes.

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.