Overdose symptoms and positive affect in never-established smokers are moderated by nicotine patch type: A between-subjects experimental investigation

Introduction

A growing number of studies are administering nicotine to never-established smokers in attempts to assess the effects of nicotine that are independent of withdrawal alleviation (e.g., Duke et al., 2015; Hahn et al., 2020; reviewed by Heishman et al., 2010; Knott et al., 1999). However, there has been surprisingly little formal assessment of dose and pharmacokinetic factors that can result in aversive responses to nicotine. This potential for overdose is especially true in the case of non-smokers. It has long been known that excessive and rapidly administered acute doses can cause nicotine overdose events (NODEs), including malaise, nausea, sickness, dizziness, unpleasantness, negative affect, and vomiting (Nyberg et al., 1982) and that high and rapidly administered acute nicotine doses can result in NODEs even in nicotine-dependent individuals (Gilbert et al., 1992; Seyler et al., 1984, 1986). Very little attention has been given to the potentially confounding effects of NODEs in never-established smokers (for brevity never-smokers are those smoking fewer than 100 cigarettes in their life) administered nicotine by nicotine patch, gums, and other routes. Given that NODEs are likely to decrease positive affect (PA), increase negative affect, and divert attention away from appropriate task performance in studies assessing the effects of nicotine on attention and affect, it is critical that studies use means of nicotine administration that minimize NODEs if inferences concerning the inherent effects of self-administered nicotine are to be accurately characterized and to have ecological validity. The accurate characterization of the effects of acute nicotine administration on mood and other potentially rewarding effects is important because never-smokers are the only group that can progress to becoming smokers and it is important to understand motives for progression to smoker status. Nicotine enhances dopamine in brain reward-related regions, such as the nucleus accumbens, with PA-inducing effects that have been promoted by many as critical determinants of the development-dependent smoking (Volkow et al., 2019).

There are several reasons why the better characterization of different nicotine dosing products and regimens is critically important to understanding nicotine use and treatment of nicotine dependence via smoking and other means. For example, while high doses of blood nicotine resulting from the rapid smoking of two 2.4 mg nicotine cigarettes after overnight deprivation in habitual smokers lead to large increases in blood beta-endorphin (BE) concentrations, minimal or no increases have been observed after the smoking of normal-nicotine delivery cigarettes smoked at more normal rates (Gilbert et al., 1992, 1994). Of note, BE, like cortisol and adrenocorticotropic hormone (ACTH), have been found to correlate strongly with the degree of aversive symptoms (e.g., nausea, sickness, and unpleasantness) in such studies (Gilbert et al., 1992; Seyler et al., 1984, 1986) associated with the smoking of high nicotine-delivery (e.g., 2.4 mg) cigarettes. Self-reported NODEs (e.g., nausea, sickness, and unpleasantness) increased after smoking two 2.4 mg nicotine cigarettes in rapid succession and subjective distress was correlated with changes in blood BE and cortisol. However, more natural smoking of a single regular (1.0 mg) cigarette did not increase blood BE or cortisol or subjective distress in a study by Gilbert et al. (1992). Overall, these findings indicate the critical importance of dose in determining the effects of nicotine in smokers, but there is no characterization of the effects of these dosing parameters in never-smokers and non-smokers.

Nonetheless, because of the lack of formal assessment of NODEs in the previous studies in never-smokers, the present study assessed NODEs formally by questionnaire every 20 minutes beginning 20 minutes after patch application in an investigation designed to assess the effects of nicotine on mood and attentional processes in never-smokers. The present report first describes the prevalence and severity of NODEs during the two-hour period after patch administration for two different brands of 7 mg nicotine patches, one with slow-rise and one with a fast-rise blood nicotine concentration, with nominally the same 24-hour nicotine delivery but with different pharmacokinetic properties.

Methods

Results

All 67 participants completed all five timepoints. There was a three-way interaction, F(2.14, 89.78) = 10.24, p < .001, ${\mathrm{\eta }}_{\mathrm{p}}^2$ = .196, involving patch type, condition, and time (Stone, 2022). There were significant simple effects for the fast-rise patches between conditions at 60, 80, and 100 minutes after patch administrations, ps < .001 (see Figure 1). At these times after patch administration, individuals who used the fast-rise nicotine patch reported significantly more NODEs compared to when they received the placebo patch. For the PA scale, there was a three-way interaction, F(2.84, 119.31) = 3.19, p = .028, ${\mathrm{\eta }}_{\mathrm{p}}^2$ = .071, such that there were significant simple effects for the fast-rise patches between conditions at 60, 80, and 100 minutes after patch administrations, ps < .016 (see Figure 2), such that individuals who used the fast-rise nicotine patch reported significantly less PA compared to when they received the placebo patch. There were no significant differences between the placebo patch and the slow-rise nicotine patch at any time points for either scale, ps > .396.

Figure 1. Nicotine overdose symptoms between patch type and condition across 100 minutes after patch application.

Mean NODE scores between the two patch types (slow-rise vs. fast-rise) by condition (nicotine vs. placebo patch) across the five time points in 20-minute intervals in a three-way ANOVA. The results show a large effect of NODEs between the fast-rise compared to the placebo conditions, where only the fast-rise patches caused significant NODEs. NODE, nicotine overdose event.

Figure 2. PA between patch type and condition across 100 minutes after patch application.

Mean PA scores between the two patch types (slow-rise vs. fast-rise) by condition (nicotine vs. placebo patch) across the five time points in 20-minute intervals in a three-way ANOVA. The results show a large effect of PA between the fast-rise compared to the placebo conditions, where only the fast-rise patches caused a significant reduction in PA. PA, positive affect.

We assessed the prevalence of NODEs by comparing baseline scores to that of T5. We used a mean score change of 2 points to determine which participants experienced NODEs or a reduction in PA. The findings suggest that in never-smokers, the lowest dose (7 mg) of rapid blood nicotine-rise patches are associated with a high prevalence of NODEs (45.83%) and decreased PA (54.17%) compared to a placebo patch (8.34% for NODEs and 33.34% for PA). Note that none of the items were significantly more endorsed than the others (i.e., these changes in NODEs and PA were not driven by a single item).

Discussion

The current investigation is to compare the subjective effects of two different commonly used nicotine patches in never-established-smokers. We found that never-smokers reported significantly more NODEs and less PA compared to placebo. These effects were not found in never-smokers who received the slow-rise nicotine patch during our two-hour assessment period. Never-smokers in the present study experienced adverse NODEs, such as nausea and feeling of sickness, when placed on the nicotine patch that produces a rapid increase in blood-nicotine concentration. Below we briefly address the potential implications of these findings, the limitations of the current study, and directions for future research.

The present findings are consistent with previous studies on habitual smokers that have shown that forcing regular smokers to consume nicotine more quickly than their typical rate can lead to nausea and even vomiting (e.g., Gilbert et al., 1992) smoke more intensely. For example, administering nicotine too quickly or in too high of doses can produce NODEs. There is a fine line between beneficial and distress-producing doses (Gilbert et al., 1992). Small differences in nicotine dosing (e.g., doubling the dose) can produce large differences in subjective and physiological effects (Gilbert et al., 1992) that make NODE-related findings ecologically invalid. Administering nicotine too quickly or in too high of doses can produce NODEs. Because habitual smokers typically do not experience NODEs when using nicotine, it is suggested that the doses of nicotine that produce NODEs may not be ecologically valid in many cases. The present results call into question the results of studies using fast-rise nicotine patches in non-smokers (e.g., Griesar et al., 2002; Sørensen et al., 2009). NODEs in nicotine research may interfere with the detection of potential reinforcing, affect-modulating, and attention-enhancing effects of nicotine and be correlated with abnormal neural and hormonal activity, limiting ecological validity.

For practical purposes, most laboratory studies of acute dosing effects in never-smokers use experimental sessions that last no more than half a day each, a period that included nicotine administration followed by mood and experimental tasks. In addition, blood nicotine level figures from the pharmacogenetics study (Gupta et al., 1995) show that fast-rise patches produce elevations at two hours that are twice as high as the slow-rise patches. However, eight hours after application the two patches produce equally high blood nicotine concentrations. The time trajectories of NODEs across this period are not known. Given that rapid tolerance develops to acute nicotine, it is not clear whether the slow-rise patches would ever produce a substantial prevalence of NODEs or for how long a duration NODEs would be sustained in rapid-rise participants. It would likely be fruitful to examine NODE time courses and to evaluate self-paced and other means of nicotine administration (e.g., electronic cigarettes or inhalers) in never-smokers. We believe that it is critically important for future acute administration studies to systematically assess NODEs using our measure or similar measure to help ensure that they are not adversely affecting study outcomes and conclusions.

The findings have a few limitations and future directions. First, we stopped data collection for the never-smokers who received the fast-rise nicotine patches because the patches were making the participants significantly sick (e.g., several participants felt they might vomit), something that we feared would prevent the accurate assessment of the effects of nicotine on PA. Thus, individuals were not randomized to the two patch types. However, it is important to note that the subjects were from the same larger subject pool (all recruitment procedures and acceptance criteria remained the same for the two samples), there was no recruitment break between the samples, and the two groups did not differ in terms of demographics.

Further, despite the dates of data collection occurring in the early 2000s, the results should not be affected by changing cultural factors since the data were collected. The NicoDerm and Habitrol patches are still being used in studies and sold over the counter. Thus, our findings are still relevant and may be even more relevant as researchers continue to use fast-rise patches with never-established smokers, despite the loss of ecological validity from the excessive presence of NODEs in their participants.

In conclusion, our findings make an important contribution to the literature in that they underline the oft-neglected importance of carefully and routinely characterizing NODEs because even subtle differences in dosing methods can lead to adverse effects on mood state. The first author noted this some 30 years ago in the case of experimental demands for high levels of smoking-delivered nicotine intake that result in NODEs in dependent smokers (Gilbert et al., 1992). Whatever the assessed subject group, it is critical that researchers to avoid using experimental demands that result in rapidly rising or high blood concentrations of nicotine that cause NODEs and altered cognitive and affective states.

Data availability