Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 May 1.
Published in final edited form as: Psychopharmacology (Berl). 2020 Jan 29;237(5):1359–1369. doi: 10.1007/s00213-020-05463-6

Differential effects of nicotine delivery rate on subjective drug effects, urges to smoke, heart rate and blood pressure in tobacco smokers

Kevin P Jensen 1,2, Gerald Valentine 1,2, Ralitza Gueorguieva 3, Mehmet Sofuoglu 1,2
PMCID: PMC7386792  NIHMSID: NIHMS1606417  PMID: 31996940

Abstract

Rationale

The nicotine delivery rate is a key feature of tobacco product design, yet there have been limited human studies examining the effects of nicotine as a function of delivery rate.

Objective

We developed an intravenous nicotine infusion protocol to evaluate differential effects of nicotine delivery rate on subjective drug effects, smoking urges, abstinence symptoms, heart rate and blood pressure.

Methods

Eighteen non-treatment seeking, overnight abstinent male and female smokers (18 to 30 year-old), who smoked ≥ 5 cigarettes per day for the past year completed four sessions in which they were randomly assigned to a saline infusion, or a 1 mg per 70 kg body weight dose of nicotine delivered over 1, 5 or 10 minutes at rates of 0.24, 0.048 or 0.024 μg/kg/second, respectively.

Results

Smoking urges, as assessed by the Brief Questionnaire of Smoking Urges, were reduced relative to placebo for the 1 and 5 min infusion, but not the 10 min infusion. Although the 1 and 5 min infusions reduced smoking urges to a similar extent, the 1 min infusion induced a greater heart rate and blood pressure increase. Changes to subjective drug effects, heart rate and blood pressure delineate the differential effects of nicotine delivery rate for these outcomes.

Conclusions

We have characterized the delivery rate-response curve for a nicotine dose that is roughly the amount of nicotine (~1 mg) delivered by smoking a standard tobacco cigarette. Our findings reinforce the importance of nicotine delivery rate when evaluating the potential effects of nicotine from tobacco products.

Keywords: Tobacco, harm reduction, nicotine, reinforcement

INTRODUCTION

Nicotine, the main addictive ingredient of tobacco, facilitates the development and maintenance of tobacco use disorder (TUD)(Benowitz 2008; Benowitz and Jacob 1984). Nicotine, as nicotine replacement therapy (NRT), helps smokers quit smoking. As NRT, nicotine’s therapeutic efficacy is presumably due to alleviation of urges to smoke and suppression of abstinence symptoms, including anxiety, depressed mood, irritability and difficulty concentrating (Gómez-Coronado et al. 2018).

Preclinical studies have shown that rapid delivery to the brain enhances the reinforcing effects of drugs of abuse including cocaine, opioids and nicotine, possibly by increasing psychomotor sensitization and immediate early gene expression (Samaha et al. 2005). In human studies, rate of delivery is positively correlated with effects linked to abuse liability (e.g., subjective good drug effects and euphoria) for cocaine (Abreu et al. 2001), morphine (Marsch et al. 2001), and diazepam (De Wit et al. 1993). For nicotine, the contribution of delivery rate to nicotine reinforcement is less clear. Tobacco cigarettes deliver nicotine rapidly and have a high abuse potential (Berridge et al. 2010). The important role of delivery rate on reinforcement is supported by preclinical studies that show faster IV nicotine infusion rates are associated with greater self-administration in rats and monkeys (Wakasa et al. 1995; Wing and Shoaib 2013), while in humans faster rates are generally associated with greater abuse potential (Henningfield and Keenan 1993; Ruther et al. 2018). Early versions of e-cigarettes deliver no nicotine or nicotine at a slower rate than tobacco cigarettes (Bullen et al. 2010; Vansickel et al. 2010). Although some early e-cigarettes can induce positive subjective effects, dual users rate tobacco cigarettes as more pleasurable than early version e-cigarettes (Norton et al. 2014). However, newer versions of e-cigarettes approach the nicotine delivery kinetics of tobacco cigarettes (Breland et al. 2017). Therefore, it is important to understand the factors that influence the speed and efficiency of nicotine delivery given the potential effects of these factors on tobacco product abuse liability (Henningfield et al. 2011).

As a potential benchmark for assessing the abuse potential of e-cigarettes, Shihadeh and Eissenberg proposed nicotine delivery rate, or “nicotine flux”, as the most critical factor for their abuse potential (Shihadeh and Eissenberg 2015). Accordingly, if an e-cigarette yields nicotine at rates above a certain, yet undetermined, threshold it can have high abuse potential and maintain addiction. In contrast, if the nicotine delivery rate is optimal, that e-cigarette product may have low addiction potential while providing sufficient nicotine delivery to help smokers quit smoking by alleviating urges to smoke. This idea is further supported by the fact that alleviation of urges to smoke or tobacco abstinence symptoms seem to be less dependent on the rate of nicotine delivery, since all nicotine products ranging from tobacco cigarettes, e-cigarettes to NRT alleviate smoking urges and abstinence symptoms (Perkins et al. 2004; Schneider et al. 2004). Based upon these observations, it seems that nicotine delivery rate correlates with the degree of abuse potential, but less with the alleviation of urges to smoke or abstinence symptoms. The proposed impact of nicotine delivery rate on nicotine’s abuse potential and its effects in alleviating urges to smoke has yet to be empirically validated in controlled human studies. To better characterize the impact of delivery rate on nicotine’s acute effects on multiple outcomes in humans, a nicotine delivery system that allows precise control over nicotine delivery rate is desirable.

Here, we used intravenous (IV) nicotine infusion to evaluate the effects of nicotine as a function of nicotine delivery rate. As supported by multiple studies, IV nicotine infusion is an optimum method to examine the influence of nicotine delivery rate on a range of outcomes due to precise control over dose and delivery rate. The effects of 1 mg/70 kg nicotine, delivered over 1, 5, or 10 minutes, were compared to saline in smokers. The 1, 5, and 10 minute delivery conditions correspond to 1 mg/70 kg nicotine at rates of 0.24 μg/kg/s, 0.048 μg/kg/s, and 0.024 μg/kg/s, respectively. Smoking a typical tobacco cigarette delivers around 1 mg of nicotine (ranging from 0.5 to 2 mg) (Djordjevic et al. 2000). Participants were overnight abstinent tobacco smokers and effects on smoking urges, abstinence symptoms, subjective drug effects, and cardiovascular outcomes (heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were assessed. The study aimed to determine differential effects of nicotine delivery on measures of abuse potential (subjective drug effects), cardiovascular activation (HR, SBP and DBP), and therapeutic effects (alleviation of smoking urges and abstinence symptoms). We hypothesized that faster nicotine delivery would be associated with greater subjective and cardiovascular effects, as well as greater alleviation of smoking urges and abstinence symptoms.

METHODS

Participants

Participants were recruited from the New Haven, Connecticut area to participate in the laboratory study. Recruitment and enrollment took place from January 2017 to January 2018. All participants provided written informed consent before participating in the study, and participants were paid for their participation. Institutional review boards at Yale University and the VA Connecticut Healthcare System approved the study. Of the 21 participants that were enrolled in the study, 18 participants (8 male,10 female) completed the study, 2 dropped out, and 1 was excluded for non-abstinence from drugs other than nicotine. The mean age was 25.7 (SD=2.6, range 22–30) years. All participants reported smoking ≥ 5 cigarettes/day for the past year, had urine cotinine levels > 100 ng/mL consistent with daily smoking, and were not seeking smoking cessation treatment. The participants had no major medical problems as determined by a self-report, a physician’s health check, and laboratory testing. Participants who had a current psychiatric disorder, including dependence on alcohol or drugs (other than nicotine) based on an evaluation with the Structured Clinical Interview for DSM-IV, were excluded from the study. A urine drug screen confirmed recent abstinence from drugs other than nicotine. Individuals on psychotropic medication, or who were pregnant or breastfeeding, were also excluded. Participant information is included in Table 1.

Table 1.

Sample characteristics.

Mean age (SEM) 25.7 (0.6)
Mean cigarettes per day (SEM) 9.7 (1.1)
Mean Fagerstrom Test for Nicotine Dependence (SEM) 4.5 (0.5)
Mean body mass index 28.0 (1.4)
% Male (n) 0.4 (8)
% African American ancestry (n) 0.9 (16)
Open in a new tab

Laboratory procedure

Participants completed four separate experimental sessions on four separate days with each session beginning around 8 AM. The experimental sessions were conducted in the Biostudies Unit located at the West Haven campus of the VA Connecticut Healthcare System. Before each experimental session, participants were required to abstain from smoking for ~10 hours, which was verified by testing to ensure that expired air carbon monoxide levels were ≤ 10 parts per million. The four infusion conditions were assigned randomly by the VA pharmacy and included either saline or nicotine at 1 mg per 70 kg body mass delivered with three different infusion durations, 1 min, 5 min and 10 min. We selected one active dose of nicotine, 1.0 mg per 70 kg body weight, and placebo (saline) because the 1.0 mg per 70 kg body weight nicotine dose approximates the total nicotine dose delivered to a smoker when they smoke a typical tobacco cigarette (Djordjevic et al. 2000). An indwelling catheter was inserted into an antecubital vein for drug administration. All infusions lasted 10 minutes and were controlled by two infusion pumps, a saline infusion pump and a nicotine infusion pump. The infusion pumps, in combination with a stop-cock valve, were engaged to maintain continuous infusion conditions of either saline or nicotine solution for 10 minutes for all conditions. For example, the 1 min nicotine infusion was followed by a 9-min saline infusion. To ensure that participants remained blinded to each experimental condition, mock adjustments were systematically made to the infusion pump and valves so that the infusion procedure appeared similar across all conditions. For example, the 10-minute saline and nicotine conditions included mock adjustments to the infusion lines and pump at minutes 1 and 5 to mimic procedural changes that would occur during those conditions. For all nicotine conditions, nicotine infusion started at minute 0, and, if necessary, saline was administered after the completion of the nicotine infusion. There were no adverse events reported. The study was registered at clinicaltrials.gov (NCT03134339).

Outcomes

For each session, participants completed the Minnesota Nicotine Withdrawal Scale (MNWS) and the Brief Questionnaire of Smoking Urges (B-QSU) after the indwelling catheter was inserted (Cox et al. 2001; Toll et al. 2007). The MNWS and B-QSU were also assessed 30 min, 60 min and 120 minutes after the start of each 10-minute infusion condition. The 8 individual MNWS responses were rated on a visual 100-mm scale, from ‘not at all’ to ‘extremely’, that was then converted to a numeric rating from 1 to 100 and summed. The 10–item B-QSU was rated with values of 0–7 for each item on the questionnaire and then summed(Cox et al. 2001; West and Ussher 2010). We also analyzed B-QSU responses clustered into two factors that reflect desire to smoke for positive reinforcing effects (Factor 1) and desire to smoke to for negative reinforcing effects (Factor 2) (Cox et al. 2001). Participants completed a Drug Effects Questionnaire (DEQ) prior to the start of each infusion and at 14 time points after the infusion started, starting at minute 1 and ending at minute 120. Each individual DEQ response was rated on a visual 100-mm scale that was then converted to a rating from 1 to 10. The DEQ ‘Aversive’, ‘Pleasurable’, and ‘Stimulatory’ outcomes were averages of three correlated DEQ assessments that we previously demonstrated to be highly correlated (Jensen et al. 2015b; Morean et al. 2013). The “Aversive” outcome was the average of ‘feel anxious’, ‘feel down’, and ‘feel bad’; the “Pleasurable” outcome was the average of ‘like’, ‘feel good’, and ‘want more’; and the “Stimulatory” outcome was the average of ‘feel stimulated’, ‘feel effects’, and ‘feel high’. HR, SBP and DBP were monitored and recorded at the intervals described below.

Data analysis

Statistical analyses were conducted using SAS version 9.4. Data were analyzed for the 18 participants that completed the study. Responses for smoking abstinence (B-QSU and MNWS) were assessed at the pre-infusion baseline and at 30, 60 and 120 minutes post-infusion, while DEQ responses were assessed at 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 30, 60 and 120. HR, SBP and DBP were assessed at 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 25, 30, 40, 50, 60 and 120 minutes post-infusion. The dependent variable was a change score that was calculated as the change in each response from pre-infusion baseline to each timepoint for the saline and nicotine conditions. The pre-infusion baseline assessment was immediately before the start of each infusion. Each dependent variable was analyzed using a mixed effects model with within participant factors of delivery rate, time, the interaction between condition and time, and main effects of session, sex and race. Random effects for participant and structured variance-covariance matrices for the repeated measures on each participant within session were used to account for the correlation structure of the data. The best-fitting structure for each outcome was selected based on the Schwartz-Bayesian Information Criterion (BIC). Least square means and standard errors were calculated to describe the patterns of means for each outcome. Pairwise comparisons of least square means were used to describe significant main effects of delivery rate and interactions of delivery rate with time.

RESULTS

Differential effects of nicotine delivery rate on alleviation of smoking urges and abstinence symptoms.

Change in B-QSU was associated with infusion condition (Figure 1A) (F(3,45)=3.75, p=0.02). B-QSU scores decreased relative to saline for nicotine delivered over 1 and 5 mins, but not over 10 mins (estimated mean change relative to saline M(SE) = −2.84 (1.90), t=−1.50, df=45, p>0.1; M(SE) = −6.17 (1.92) t=−3.21, df=45, p< 0.01; and M(SE) = −4.48 (1.90), t=−2.35, df=45, p<0.01 for 10 min, 5 min and 1 min conditions, respectively). There were no significant differences in B-QSU scores among the three different nicotine delivery durations. Factor 2 of the B-QSU, which assesses desire to smoke to alleviate negative affect, was associated with infusion condition (F(3,45)=7.38, p< 0.001). Factor 2 was decreased relative to saline when nicotine was infused over 1 min (M(SE) = −2.55 (0.88), t=−−2.90, df=45, p<0.01), 5 mins (M(SE) = −3.91 (0.89), t=−4.41, df=45, p< 0001), and 10 mins (M(SE) = −3.15 (0.88), t= −3.60, df=45, p<0.01). There were no differences in factor 2 when comparing the three different nicotine infusion durations to each other. Factor 1 of the B-QSU, which assesses desire to smoke for positive reinforcing effects, was not associated with infusion condition (i.e. no difference between saline and nicotine conditions). Factor 1 and 2 responses are shown in Figure S1. There were also no effects on MNWS scores (Figure 1B).

Figure 1. The effect of nicotine infusion rate on nicotine abstinence symptoms.

Figure 1.

Open in a new tab

The mean change in scores from the pre-infusion baseline for (A) Brief Questionnaire on Smoking Urges (B-QSU) and (B) Minnesota Nicotine Withdrawal Scale (MNWS) in response to saline and nicotine (total dose, 1.0 mg per 70 kg body weight) infused over 1 min, 5 min and 10 min. Error bars reflect standard error of the mean.

Differential effects of nicotine delivery rate on subjective drug effects.

The effect of nicotine delivery duration on the subjective stimulatory, pleasurable and aversive effects of nicotine are shown in Figure 2. The responses for individual DEQ items that were used to create the stimulatory, pleasurable and aversive outcomes are shown in Figure S2-4. There were significant effects on ratings of stimulatory effects (F(3,77.5)=4.23, p<0.01). Stimulatory effects were greater relative to saline when nicotine was infused over 1 min (M(SE) = 11.22 (3.86), df=77.6, t=2.90, p <0.01), 5 mins (M(SE) = 8.19 (3.85), df=77.5, t=2.12, p < 0.05), and 10 mins (M(SE) = 12.43 (3.84), df=77.3, t=3.24, p <0.01). There were no differences in stimulatory effects when comparing the three different nicotine infusion durations to each other, however, there was a significant interaction of delivery condition and time (F(36,382)=2.86, p<.0001) that revealed robust differences between the different nicotine delivery durations at certain timepoints. The results of pairwise comparisons of stimulatory effects at each minute for each nicotine delivery duration versus the saline condition are shown in Figure 2A. The results of pairwise comparisons among the three different nicotine delivery durations are summarized in Figure 4. Most notably, at the 1 min timepoint, the 1 min nicotine duration had greater ratings of stimulation than the 5 and 10 min nicotine durations (p<0.05).

Figure 2. The effects of nicotine infusion rate on subjective drug effects.

Figure 2.

Open in a new tab

The mean change from baseline for subjective (A) stimulatory, (B) pleasurable, (C) like, and (D) aversive effects in response to infusion of saline and nicotine (total dose, 1.0 mg per 70 kg body weight) infused over 1 min, 5 min and 10 min. Responses are shown for the first 30 minutes of a 120 minutes session. Error bars reflect standard error of the mean.

Figure 4. Pairwise comparisons between nicotine infusion conditions.

Figure 4.

Open in a new tab

Shown are the results of pairwise tests between nicotine infusion conditions at each minute post infusion for outcomes with minute by condition effects that were significant (p <0.05). The −Log10(P) value was multiplied by the effect direction for the comparison described in the legend; for example, a positive value on the y-axis indicates that the first condition was greater than the second. Shown are comparisons over the first 18 min of the 120 min assessment period. No effects were significant after 18 min. P = 0.05 is marked by the dashed line.

For pleasurable effects, there was a significant main effect (F(3,77.3)=4.17, p<0.01), with greater increases, relative to saline, for nicotine infused over 1 min (M(SE) = 9.20 (4.12), df=77.5, t=2.24, p<0.05), 5 mins (M(SE) = 11.18 (4.11), df=77.3, t= 2.72, p< 0.01) and 10 mins (M(SE) = 13.50 (4.09), df=76.9, t=3.30, p<0.01). An interaction of delivery condition and time (F(36,356)=1.58, p=.02) reflected differences among the conditions at certain timepoints. Figure 2C shows the change for the single DEQ ‘like’ item. This specific response is considered important for evaluating abuse potential (US Food and Drug Administration (FDA) 2017). The responses to ‘like’, ‘feel good’ and ‘want more’ formed the ‘pleasurable’ effects outcome. For the single ‘like’ outcome there was a significant interaction of delivery condition and time (F(36,62)=2.47, p<0.01), but no significant effect of condition (F(3,35.2)=2.26, p>0.05). The results of pairwise comparisons of pleasurable and like effects at each timepoint are shown in Figure 2B–C and 4. The changes in aversive effects were modest and no significant effects were observed on this outcome (Figure 2D).

Differential effects of nicotine delivery rate on heart rate and blood pressure.

The effects of nicotine delivery duration on HR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) are shown in Figure 3. There were significant effects on change in HR (F(3,118)=18.18, p<.0001). HR was higher relative to saline when nicotine was infused over 1 min (M(SE) = 8.88 (1.50), df=118, t=5.93, p<0.0001), 5 mins (M(SE) = 6.44 (1.44), df=119, t= 4.47, p< 0.0001) and 10 mins (M(SE) = 9.85 (1.45), df=117, t=6.79, p<0.0001). Among the three different nicotine infusion durations, the overall HR increase for the 5 min duration was significantly less than the 10 min duration (M(SE) = 3.4 (1.40), df=118, t=−2.41, p<0.05). For change in HR, there was also a significant interaction between delivery condition and time (F(45, 372)=3.36, p<.0001) showing differences between the different nicotine delivery durations at certain timepoints. The results of pairwise comparisons of HR effects at each timepoint are shown in in Figures 3A and 4. Most notably, the rapid HR increase at the 2 and 5 min timepoints for the 1 min delivery duration were greater than those for the 5 and 10 min delivery duration (p<0.05).

Figure 3. The effects of nicotine infusion rate on heart rate and blood pressure.

Figure 3.

Open in a new tab

The mean change from baseline for (A) heart rate (beats per minute), (B) diastolic blood pressure (mmHg), and (C) systolic blood pressure (mmHg) in response to infusions of saline and nicotine (total dose, 1.0 mg per 70 kg body weight) infused over 1 min, 5 min and 10 min. Error bars reflect standard error of the mean. Responses are shown for the first 30 minutes of a 120 minutes session.

There were significant effects on change in DBP (F(3,121)=4.72, p=.004). Changes in DBP were greater relative to saline for nicotine infused over 1 min (M(SE) = 7.34 (2.19), df=121, t=3.36, p<0.01), 5 mins (M(SE) =6.66 (2.11), df=121, t=3.16, p<0.01) and 10 mins (M(SE) =4.68 (2.13), df=120, t=2.20, p<0.05). There were no differences in DBP change when comparing the three different nicotine delivery durations to each other. However, for change in DBP there was a significant interaction between condition and time (F(45,227)=1.87, p=0.002) that revealed differences between the different nicotine delivery durations at certain timepoints. The results of pairwise comparisons of DBP effects at each timepoint are shown in Figures 3B and 4. For the 1 min delivery duration, the DBP increase was greater than the 10 min delivery duration at the 1 minute timepoint and greater than 5 and 10 min delivery duration at the 2 minute timepoint (p<0.05). There were significant effects on change in SBP (F(3,128)=8.46, p<.0001). Changes in SBP are show in Figure 3C. SBP changes were greater relative to saline for nicotine infused over 1 min (M(SE) = 7.86 (1.59), df=127, t=4.94, p<0.0001) and 10 mins (M(SE) =4.33 (1.54), df=127, t=2.81, p<0.001). When comparing SBP effects between different nicotine delivery durations, the 1 min duration was significantly greater than 5 min duration(M(SE) =5.03 (1.56), df=127, t=3.22, p<0.001) and the 10 min duration (M(SE) =3.53 (1.56), df=127, t=2.26, p<0.05). For SBP there was no significant interaction between condition and time.

DISCUSSION

Using an IV nicotine infusion protocol, we evaluated the effects of nicotine as a function of nicotine delivery rate in a sample of overnight abstinent smokers. The main finding was that nicotine’s effects in inducing positive subjective and cardiovascular effects and alleviation of smoking urges were rate dependent such that 1 min delivery duration (nicotine at 0.24 μg/kg/s), produced the most robust effects. The 5 min delivery duration (nicotine at 0.048 μg/kg/s) alleviated smoking urges similar to the 1 min condition, but with less cardiovascular activation. The 10 min delivery duration (nicotine at 0.024 μg/kg/s) was the least effective in alleviating of smoking urges (see Table 2). To our knowledge this is the first study that examined the impact of nicotine delivery rate on subjective effects, HR and blood pressure, as well as urges to smoke cigarettes and abstinence symptoms, in abstinent smokers. The findings highlight the differential impact of delivery rate on suppression of smoking urges, subjective drug effects, and HR. Our findings also support the potential utility of nicotine delivery rate or nicotine flux when evaluating the pharmacodynamic profiles of tobacco products to assess abuse and misuse potential (US Food and Drug Administration (FDA) 2016; 2017).

Table 2.

Summary of the findings

Outcome Infusion Duration
1 min 5 min 10 min
Smoking urges ↓ ↓ -
Subjective effects ↑↑ ↑ ↑
Heart rate ↑↑ ↑ ↑
Open in a new tab

The greater subjective stimulation from the 1 min compared to the 5 and 10 min conditions are consistent with the results for other drugs of abuse including morphine, cocaine and benzodiazepines (Abreu et al. 2001; De Wit et al. 1993; Marsch et al. 2001). The rating of pleasurable effects increased relative to saline, but they were not affected by the rate of delivery. As mentioned before, among NRTs, rate of nicotine delivery was not associated with differences in subjective effects (Perkins et al. 2004). In fact, NRTs produced very modest subjective drug effects with limited abuse potential compared to cigarettes (Schuh et al. 1997). These and similar findings led to a suggestion that the reinforcing and rewarding effects of pure nicotine delivery systems, such as NRT, may not be rate dependent (Dar and Frenk 2007). Our findings using a controlled nicotine infusion procedure with a range of delivery rates demonstrates that the rate of delivery also affects the subjective effects of nicotine, similar to other drugs of abuse.

The urge to smoke as assessed by the B-QSU was reduced relative to placebo for the 1 and 5 min, but not 10 min condition. There were notable differences in the effects of rate on B-QSU factor 1 relative to factor 2. B-QSU factor 2 was reduced relative to saline for all nicotine delivery conditions, however B-QSU factor 1 was not reduced relative to saline for any nicotine condition. These findings suggest that the suppression of urges to smoke to relieve negative affect (factor 2) might be more sensitive to differences in nicotine delivery rate than suppression of urges to smoke for positive effects (factor 1) (Tiffany and Drobes 1991). Because different NRT products, in spite of their differences in rate of nicotine delivery, are similarly effective in reducing urges to smoke and abstinence symptoms, it is generally assumed that rate of delivery does not affect nicotine’s effects on these outcomes. To our knowledge, no previous study has examined if rate of delivery affects the alleviation of smoking urges by nicotine. Our findings support that faster nicotine delivery rates may be more effective in alleviating urges to smoke.

Cardiovascular activation by nicotine was also potentiated with faster delivery rate. Specifically, HR and diastolic blood pressure increases were highest for the 1 min delivery. These findings are consistent with previous studies which showed greater HR and blood pressure increases with nicotine nasal spray, than nicotine patch, which delivers nicotine slower than nasal spray (Perkins et al. 2004). Given the potential harmful cardiovascular effects of nicotine, the rate of delivery should be considered in the overall health effects of nicotine products (Babic et al. 2019).

The 1 mg/70 kg body weight dose of IV nicotine is approximately equivalent to the dose of nicotine delivered to a smoker when they smoke a typical tobacco cigarette (Djordjevic et al. 2000). A typical smoker smokes a cigarette over 5–10 minutes, thus ~1 mg nicotine is consumed via ‘puffing’ over 5–10 minutes (Rose et al. 1999). In our study a nicotine dose of approximately 1 mg was delivered at a constant rate over 1, 5 and 10 minutes. There is marked variety in nicotine delivery rates among tobacco products. There is also great variety in nicotine delivery rates among specific categories of tobacco products, for example nicotine delivery among different types of e-cigarettes has been noted to vary widely (Brown and Cheng 2014). Newer generation e-cigarettes that deliver nicotine at faster rates than older generation e-cigarettes, are rated by users as more favorable (Ruther et al. 2018). The nicotine delivery rate has been raised as one potential criteria for evaluating the potential health effects associated with tobacco products, including their potential use as harm reduction approaches to cigarette smoking (Eissenberg and Shihadeh 2015). We have characterized key aspects of the delivery rate-response curve for a dose of nicotine (~1 mg) that is roughly the amount of nicotine delivered by smoking a standard tobacco cigarette.

It will be important to understand the mechanisms that govern the differential response to nicotine delivered at different rates, as current tobacco products have a wide range of nicotine delivery rates and the potential health effects associated with different rates are uncertain (Brown and Cheng 2014). The behavioral and molecular effects of rate were investigated in a study by Samaha et al. that tested the differential effects of 25–50 ug / per kg body weight nicotine infused intravenously over 5, 25, or 100 seconds in a rodent model. Faster rates were associated with more robust effects at the behavioral and molecular level, including greater c-fos and arc induction specifically in mesocorticolimbic regions (Samaha et al. 2005). Consistent with these findings, faster rates are generally associated with greater positive effects and abuse liability in humans who consume tobacco products (Henningfield and Keenan 1993; Ruther et al. 2018). Some insight into the molecular mechanisms in humans might be gathered by studying effects of rate on participants stratified by genetic variants associated with differential response to nicotine. Potential candidates include variants identified in genomewide association studies of tobacco use disorder (Erzurumluoglu et al. 2019; Jensen et al. 2015a; Jensen et al. 2017). Studying such variation might provide links to genes and pathways that modify sensitivity to the effects of nicotine at different delivery rates.

Our findings should be considered in some context. We tested a single dose of nicotine, 1 mg per 70 kg body weight. Thus, the three rates approximate a cigarette’s worth of nicotine delivered over 10, 5 and 1 minutes. Although our findings are benchmarks for the relative effects of 1 mg per 70 kg nicotine delivered at three specific rates, the effects at lower doses (i.e. < 1.0 mg), and at variable, or intermittent, rates will be important to evaluate. IV protocols to evaluate effects of rapid intermittent nicotine delivery, or variable delivery at lower doses (< 1 mg per 70 kg) could be more sensitive, and therefore highly informative.

Direct assessments of nicotine reinforcement, such as with a nicotine self-administration procedure, are required to evaluate any potential impact of delivery rate on clinical outcomes (e.g. quitting/reducing cigarette smoking). Self-administration is considered by many to be the best paradigm or gold standard method for evaluating reinforcing effects in both animals and humans (Goodwin et al. 2015). Indeed, our findings warrant future human self-administration studies testing the effects of delivery rate on nicotine reinforcement. IV nicotine self-administration paradigms may be particularly relevant to examine the effect of delivery rate, as well as dose, on nicotine reinforcement (Jensen et al. 2016). Differential effects based on rate may be more robust in protocols with rapid intermittent nicotine delivery, or variable delivery at lower doses (< 1 mg per 70 kg) for some outcomes. For example, while we detected rate-dependent changes in B-QSU, but not in MNWS scores, this response profile may reflect the degree of abstinence as some research suggests that B-QSU may have greater sensitivity to early abstinence (24-hr) compared to the MNWS. Also, our DEQ analysis focused on correlated responses that in prior work were shown to cluster into three outcomes ‘pleasurable effects’, ‘stimulatory effects’, and ‘aversive effects’ (Jensen et al. 2015b; Morean et al. 2013). A larger study might have greater statistical power to detect effects on a more extensive panel of DEQ responses, including single item scores.

The participants in our study were daily smokers that were at least overnight abstinent and sensitivity to rate might differ after several days or weeks of abstinence. It is also important to consider that the sample included light to moderate smokers that were overnight abstinent from nicotine. Being a non-smoker (or very light smoker) and the degree of smoking abstinence might differently affect sensitivity to nicotine delivery rate. For example, nicotine might induce greater ‘aversive’ effects in participants with no prior nicotine exposure compared to participants with prior nicotine exposure. Also, the use of CO as the only indicator of abstinence from nicotine would not have identified participants who used electronic cigarettes or other ‘smokeless’ products that contain nicotine during the required pre-study abstinence period. As such, acute tolerance induced by baseline nicotine may have affected the responses for some participants. It will be important evaluate the effect of nicotine delivery rate in light smokers and smokers that had an extended (e.g. >1 day – 1 week) period of nicotine abstinence. Also, sex differences in sensitivity to IV nicotine have been described in prior studies (DeVito et al. 2014; Jensen et al. 2016); however, the statistical power required to evaluate sex differences in this study was limited by the sample size (8 male,10 female); as such, it will be important to evaluate sex differences in the effects on delivery rate in future studies. Moreover, the generalizability of the findings might be limited, to some extent, given that the sample was mostly African American. Racial differences, including differences in nicotine metabolism and tobacco product preference, could affect the response to nicotine delivery rate (Benowitz et al. 2016; Caraballo and Asman 2011; DeVito et al. 2016; Sofuoglu et al. 2012).

With these limitations in mind, our results support the potential utility of nicotine delivery rate or nicotine flux as a target for tobacco regulation. As suggested by Shihadeh and Eissenberg, if the nicotine delivery rate or nicotine flux of a tobacco product is “optimal”, it may have a low abuse potential while providing sufficient nicotine delivery to help smokers quit smoking by alleviating urges to smoke and reducing symptoms of tobacco abstinence. In our study, the 5 min delivery rate seemed to alleviate urges to smoke similar to the 1 min rate but with less subjective drug effects from nicotine, suggesting a lower abuse potential than the 1 min delivery rate. Our findings reinforce the importance of nicotine delivery rate when considering the potential health effects of nicotine from tobacco products. It will be important to extend work on the nicotine delivery rate to include studies on the effects of rate in other populations (i.e. non-daily smokers, or ‘chippers’), the impact of flavors that are commonly used in tobacco products and to explore molecular mechanisms for the differential effects of rate.

In summary, using an intravenous nicotine infusion protocol, we characterized the effects of 1 mg per 70 kg body weight nicotine delivered at three rates. Nicotine had delivery rate dependent effects such that changes in subjective and cardiovascular effects and alleviation of smoking urges were more robust for 1 mg/70 kg nicotine delivered over 1 min compared to 10 min. The 1 and 5 min conditions each reduced smoking urges relative to placebo, however there was less cardiovascular activation for the 5 min condition.

Supplementary Material

Supplemental material

Acknowledgments:

We are grateful to Ellen Mitchell, Lance Barnes, and Stacy Minnix for providing excellent technical assistance.

Funding: Research reported in this publication was supported by grant number R03DA043004 and U54DA036151 from NIDA and FDA Center for Tobacco Products (CTP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration

Footnotes

Conflicts of Interest: Since participating in this research KPJ has become an employee of Celgene Corporation and Bristol-Myers Squibb and declares no conflict of interest. All other authors declare no potential conflicts of interest.

References

  1. Abreu ME, Bigelow GE, Fleisher L, Walsh SL (2001) Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans. Psychopharmacology (Berl) 154: 76–84. [DOI] [PubMed] [Google Scholar]
  2. Babic M, Schuchardt M, Tolle M, van der Giet M (2019) In times of tobacco-free nicotine consumption: The influence of nicotine on vascular calcification. Eur J Clin Invest: e13077. [DOI] [PubMed] [Google Scholar]
  3. Benowitz NL (2008) Clinical pharmacology of nicotine: Implications for understanding, preventing, and treating tobacco addiction. Clin Pharmacol Ther 83: 531–541. [DOI] [PubMed] [Google Scholar]
  4. Benowitz NL, Jacob P (1984) Daily Intake of Nicotine during Cigarette-Smoking. Clin Pharmacol Ther 35: 499–504. [DOI] [PubMed] [Google Scholar]
  5. Benowitz NL, St Helen G, Dempsey DA, Jacob P 3rd, Tyndale RF (2016) Disposition kinetics and metabolism of nicotine and cotinine in African American smokers: impact of CYP2A6 genetic variation and enzymatic activity. Pharmacogenet Genomics 26: 340–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berridge MS, Apana SM, Nagano KK, Berridge CE, Leisure GP, et al. (2010) Smoking produces rapid rise of [11C]nicotine in human brain. Psychopharmacology (Berl) 209: 383–94. [DOI] [PubMed] [Google Scholar]
  7. Breland A, Soule E, Lopez A, Ramoa C, El-Hellani A, et al. (2017) Electronic cigarettes: what are they and what do they do? Ann N Y Acad Sci 1394: 5–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brown CJ, Cheng JM (2014) Electronic cigarettes: product characterisation and design considerations. Tob Control 23 Suppl 2: ii4–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bullen C, McRobbie H, Thornley S, Glover M, Lin R, et al. (2010) Effect of an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross-over trial. Tob Control 19: 98–103. [DOI] [PubMed] [Google Scholar]
  10. Caraballo RS, Asman K (2011) Epidemiology of menthol cigarette use in the United States. Tob Induc Dis 9 Suppl 1: S1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cox LS, Tiffany ST, Christen AG (2001) Evaluation of the brief questionnaire of smoking urges (QSU-brief) in laboratory and clinical settings. Nicotine Tob Res 3: 7–16. [DOI] [PubMed] [Google Scholar]
  12. Dar R, Frenk H (2007) Reevaluating the nicotine delivery kinetics hypothesis. Psychopharmacology (Berl) 192: 1–7. [DOI] [PubMed] [Google Scholar]
  13. De Wit H, Dudish S, Ambre J (1993) Subjective and behavioral effects of diazepam depend on its rate of onset. Psychopharmacology (Berl) 112: 324–330. [DOI] [PubMed] [Google Scholar]
  14. DeVito EE, Herman AI, Waters AJ, Valentine GW, Sofuoglu M (2014) Subjective, physiological, and cognitive responses to intravenous nicotine: effects of sex and menstrual cycle phase. Neuropsychopharmacology 39: 1431–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. DeVito EE, Valentine GW, Herman AI, Jensen KP, Sofuoglu M (2016) Effect of Menthol-preferring Status on Response to Intravenous Nicotine. Tob Regul Sci 2: 317–328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Djordjevic MV, Stellman SD, Zang E (2000) Doses of nicotine and lung carcinogens delivered to cigarette smokers. J Natl Cancer Inst 92: 106–111. [DOI] [PubMed] [Google Scholar]
  17. Eissenberg T, Shihadeh A (2015) Nicotine flux: a potentially important tool for regulating electronic cigarettes. Nicotine Tob Res 17: 165–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Erzurumluoglu AM, Liu M, Jackson VE, Barnes DR, Datta G, et al. (2019) Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Mol Psychiatry. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gómez-Coronado N, Walker AJ, Berk M, Dodd S (2018) Current and emerging pharmacotherapies for cessation of tobacco smoking. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 38: 235–258. [DOI] [PubMed] [Google Scholar]
  20. Goodwin AK, Hiranita T, Paule MG (2015) The Reinforcing Effects of Nicotine in Humans and Nonhuman Primates: A Review of Intravenous Self-Administration Evidence and Future Directions for Research. Nicotine Tob Res 17: 1297–310. [DOI] [PubMed] [Google Scholar]
  21. Henningfield JE, Hatsukami DK, Zeller M, Peters E (2011) Conference on abuse liability and appeal of tobacco products: conclusions and recommendations. Drug Alcohol Depend 116: 1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Henningfield JE, Keenan RM (1993) Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol 61: 743–50. [DOI] [PubMed] [Google Scholar]
  23. Jensen KP, DeVito EE, Herman AI, Valentine GW, Gelernter J, et al. (2015a) A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans. Neuropsychopharmacology 40: 2813–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jensen KP, DeVito EE, Valentine G, Gueorguieva R, Sofuoglu M (2016) Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences. Neuropsychopharmacology 41: 2034–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jensen KP, Herman AI, Morean ME, Kranzler HR, Gelernter J, et al. (2015b) FKBP5 variation is associated with the acute and chronic effects of nicotine. Pharmacogenomics J 15: 340–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jensen KP, Smith AH, Herman AI, Farrer LA, Kranzler HR, et al. (2017) A protocadherin gene cluster regulatory variant is associated with nicotine withdrawal and the urge to smoke. Mol Psychiatry 22: 242–249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Marsch LA, Bickel WK, Badger GJ, Rathmell JP, Swedberg MD, et al. (2001) Effects of infusion rate of intravenously administered morphine on physiological, psychomotor, and self-reported measures in humans. J Pharmacol Exp Ther 299: 1056–1065. [PubMed] [Google Scholar]
  28. Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, et al. (2013) The drug effects questionnaire: psychometric support across three drug types. Psychopharmacology (Berl) 227: 177–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Norton KJ, June KM, O’Connor RJ (2014) Initial puffing behaviors and subjective responses differ between an electronic nicotine delivery system and traditional cigarettes. Tob Induc Dis 12: 17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Perkins KA, Lerman C, Keenan J, Fonte C, Coddington S (2004) Rate of nicotine onset from nicotine replacement therapy and acute responses in smokers. Nicotine & tobacco research 6: 501–507. [DOI] [PubMed] [Google Scholar]
  31. Rose JE, Behm FM, Westman EC, Coleman RE (1999) Arterial nicotine kinetics during cigarette smoking and intravenous nicotine administration: implications for addiction. Drug Alcohol Depend 56: 99–107. [DOI] [PubMed] [Google Scholar]
  32. Ruther T, Hagedorn D, Schiela K, Schettgen T, Osiander-Fuchs H, et al. (2018) Nicotine delivery efficiency of first- and second-generation e-cigarettes and its impact on relief of craving during the acute phase of use. Int J Hyg Environ Health 221: 191–198. [DOI] [PubMed] [Google Scholar]
  33. Samaha AN, Yau WY, Yang P, Robinson TE (2005) Rapid delivery of nicotine promotes behavioral sensitization and alters its neurobiological impact. Biol Psychiatry 57: 351–60. [DOI] [PubMed] [Google Scholar]
  34. Schneider NG, Olmstead RE, Nides M, Mody FV, Otte-Colquette P, et al. (2004) Comparative testing of 5 nicotine systems: initial use and preferences. Am J Health Behav 28: 72–86. [DOI] [PubMed] [Google Scholar]
  35. Schuh KJ, Schuh LM, Henningfield JE, Stitzer ML (1997) Nicotine nasal spray and vapor inhaler: Abuse liability assessment. Psychopharmacology (Berl) 130: 352–361. [DOI] [PubMed] [Google Scholar]
  36. Shihadeh A, Eissenberg T (2015) Electronic cigarette effectiveness and abuse liability: predicting and regulating nicotine flux. Nicotine Tob Res 17: 158–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sofuoglu M, Herman AI, Nadim H, Jatlow P (2012) Rapid nicotine clearance is associated with greater reward and heart rate increases from intravenous nicotine. Neuropsychopharmacology 37: 1509–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tiffany ST, Drobes DJ (1991) The development and initial validation of a questionnaire on smoking urges. Br J Addict 86: 1467–76. [DOI] [PubMed] [Google Scholar]
  39. Toll BA, O’Malley SS, McKee SA, Salovey P, Krishnan-Sarin S (2007) Confirmatory factor analysis of the Minnesota Nicotine Withdrawal Scale. Psychol Addict Behav 21: 216–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. US Food and Drug Administration (FDA) (2016) Draft Guidance on Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems
  41. US Food and Drug Administration (FDA) (2017) Assessment of abuse potential of drugs: guidance for industry
  42. Vansickel AR, Cobb CO, Weaver MF, Eissenberg TE (2010) A clinical laboratory model for evaluating the acute effects of electronic “cigarettes”: nicotine delivery profile and cardiovascular and subjective effects. Cancer Epidemiol Biomarkers Prev 19: 1945–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wakasa Y, Takada K, Yanagita T (1995) Reinforcing effect as a function of infusion speed in intravenous self-administration of nicotine in rhesus monkeys. Nihon Shinkei Seishin Yakurigaku Zasshi 15: 53–9. [PubMed] [Google Scholar]
  44. West R, Ussher M (2010) Is the ten-item Questionnaire of Smoking Urges (QSU-brief) more sensitive to abstinence than shorter craving measures? Psychopharmacology (Berl) 208: 427–432. [DOI] [PubMed] [Google Scholar]
  45. Wing VC, Shoaib M (2013) Effect of infusion rate on intravenous nicotine self-administration in rats. Behav Pharmacol 24: 517–22. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental material
NIHMS1606417-supplement-Supplemental_material.docx (408.6KB, docx)

RESOURCES