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. Author manuscript; available in PMC: 2022 May 10.
Published in final edited form as: Exp Clin Psychopharmacol. 2013 May 6;21(3):188–195. doi: 10.1037/a0031799

Nicotine Levels After IV Nicotine and Cigarette Smoking in Men

Nancy K Mello 1, Mackenzie R Peltier 2, Haley Duncanson 3
PMCID: PMC9086919  NIHMSID: NIHMS1798516  PMID: 23647094

Abstract

There has been considerable interest in the pharmacodynamics and pharmacokinetics of nicotine and the influence of different routes of administration. However, these variables are often examined in separate studies, and there is less information about the temporal relation between subjective reports and plasma nicotine levels. This study examined the time course and magnitude of plasma nicotine levels and reports of subjective “high” in nicotine-dependent men after 12 or more hrs of abstinence. The effects of two doses of IV nicotine and two doses of nicotine from cigarette smoking were compared, and samples were collected at 2-min intervals. Plasma nicotine levels after smoking a high-nicotine cigarette were significantly greater than after either dose of IV nicotine (p < .001). However, Visual Analog Scale (VAS) ratings of “high” after both doses of IV nicotine and smoking a high-nicotine cigarette did not differ significantly, and followed a similar time course. After smoking a low-nicotine cigarette, VAS ratings of “high” were significantly lower than after either IV nicotine dose or smoking a high-nicotine cigarette (p < .001). Peak levels of “high” were reported within 2 min after IV nicotine administration and the onset of cigarette smoking. Then “high” ratings abruptly decreased, while plasma nicotine rose to peak levels within 4 to 6 min after IV nicotine and 12 to 14 min during cigarette smoking. Plasma nicotine levels did not appear to determine the magnitude or time course of subjective effects under these conditions.

Keywords: nicotine, cigarette smoking, IV nicotine, visual analog scale, blood nicotine levels

The subjective and physiological effects of intravenous nicotine have been studied in smokers and nonsmokers (Soria et al., 1996) and have been compared with the effects of cocaine (Jones, Garrett, & Griffiths, 1999) and caffeine (Garrett & Griffiths, 2001). One early study compared the subjective and physiological effects of IV nicotine with nicotine from cigarette smoking (Henningfield, Miyasato, & Jasinski, 1985). It was concluded that across the dose range studied, the temporal patterns, duration, and magnitude of physiologic and subjective responses were similar after IV nicotine administration and cigarette smoking (Henningfield et al., 1985). Interestingly, one purpose of that study was to determine if nicotine was psychoactive and to assess its possible abuse liability. The conclusion that “nicotine is a prototypic drug of abuse” has been consistently reaffirmed over the past 27 years.

Although these pioneering clinical laboratory studies provided a comprehensive analysis of the pharmacodynamics of nicotine, none reported plasma nicotine levels. One goal of the present study was to compare plasma nicotine levels after cigarette smoking and IV nicotine administration in nicotine-dependent men. Blood samples were collected and analyzed under uniform conditions after both routes of nicotine administration. We have previously reported that plasma nicotine levels after cigarette smoking were dose-related, and well correlated with neuroendocrine, physiologic and subjective measures (Mello, 2010; Mendelson, Goletiani, Sholar, Siegel, & Mello, 2008; Mendelson, Sholar, Goletiani, Siegel, & Mello, 2005). Because neuroimaging studies of the effects of nicotine usually use an IV route of nicotine administration (Rose, Ross, Kurup, & Stein, 2010; Stein, 2001; Stein et al., 1998; Yamamoto et al., 2012), it is useful to know how nicotine plasma levels compare after cigarette smoking and IV nicotine.

A second goal of the current study was to compare the temporal covariance between subjective reports of “high” and plasma nicotine levels after IV nicotine administration and cigarette smoking. There has been considerable interest in the rate of onset of nicotine’s effects after various routes of administration, and the implications for behavior (see for review (Henningfield & Keenan, 1993). The subjective effects of various drugs are influenced in part, by the rate at which drug concentrations increase in brain. A number of clinical studies suggest that the faster a drug enters the brain, the more intense the positive subjective effects, e.g.” high,” “ liking” tend to be (Abreu, Bigelow, Fleisher, & Walsh, 2001; de Wit, Bodker, & Ambre, 1992; Henningfield & Keenan, 1993; Lunell & Curvall, 2011; Marsch et al., 2001). However, most studies of nicotine have relied on reports of subjective effects and have not measured drug levels in blood.

This study compares the effects of a low and high dose of IV and smoked nicotine in 35 nicotine-dependent men. The dependent measures were plasma nicotine levels and reports of subjective “high” on a Visual Analog Scale (VAS). Blood samples and subjective reports were collected every 2 min for the first 16 or 20 min after nicotine administration began. Samples were collected frequently to facilitate comparisons between the time course of plasma nicotine levels and reports of subjective “high” after IV and smoked nicotine administration.

Materials and Method

Subjects

Thirty-five healthy adult men were recruited through newspaper and Internet advertisements and provided written informed consent for prestudy procedures and for participation in two studies. The smoking study compared men who smoked either a high- or low-dose nicotine cigarette (Mendelson et al., 2005). The IV nicotine compared men who received either 1.5 mg/70kg or 1.0 mg/70kg of IV nicotine (not previously published). Both studies used the same blood sampling and VAS measurement procedures, smoking abstinence requirements, subject exclusion and inclusion criteria, and cardiovascular and safety precautions. The current report is a comparison of the entire data set across both studies to compare the effects of IV and smoked nicotine in these samples.

The study was approved by the Institutional Review Board of the McLean Hospital. All men fulfilled American Psychiatric Association Diagnostic and Statistical Manual (DSM–IV) criteria for current nicotine dependence (305.1). Volunteers with any lifetime DSM–IV Axis I disorder other than nicotine dependence were excluded. Men who were seeking treatment for nicotine dependence or who were wearing a nicotine patch were also excluded.

All men were in good physical health and had normal medical and laboratory screening examinations. Volunteers did not differ significantly with respect to age, years of smoking, number of cigarettes smoked per day and body mass index (BMI) (Table 1). A between-subjects design was used in both studies, because it was difficult to retain nicotine-dependent men. In the IV nicotine study, nine men were administered 1.5 mg/70 kg IV nicotine, and six men were administered 1.0 mg/70 kg IV nicotine. In the cigarette smoking study, 10 men were randomly assigned to smoking a high-nicotine cigarette and 10 men were assigned to smoking a low-nicotine cigarette.

Table 1.

Subject Characteristics

Age (years) Years of smoking Cigarettes smoked/day BMI Baseline CO levels Baseline plasma nicotine levels
High-nicotine cigarette group (n = 10) 25.6 ± 1.1 6.7 ± 0.7 16.5 ± 1.0 24.1 ± 0.6 3.4 ± 0.8 1.61 ± 0.2
Low-nicotine cigarette group (n = 10) 25.2 ± 0.8 5.0 ± 0.3 15.0 ± 0.5 24.8 ± 0.4 3.7 ± 0.7 1.20 ± 0.2
High-IV-nicotine group (n = 9) 25.9 ± 0.8 9.5 ± 2.4 19.6 ± 2.2 25.8 ± 0.8 3.6 ± 1.1 1.33 ± 0.6
Low-IV-nicotine group (n = 6) 28.0 ± 3.1 10.6 ± 3.2 21.8 ± 4.5 24.9 ± 0.8 4.2 ± 0.8 0.65 ± 0.5
ANOVA results p = .58 F(3, 34) = 0.662 p = .11 F(3, 34) = 2.165 p = .11 F(3, 34) = 2.157 p = .25 F(3, 34) = 1.429 p = .95 F(3, 34) = 0.123 p = .39 F(3, 34) = 1.038
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The study procedures were explained during initial screening and again on the study day, and any questions or concerns were discussed. Volunteers were admitted to the clinical research ward on the morning of the study day, and all studies were conducted at the same time of day. In the IV nicotine study, volunteers were told that an intravenous dose of nicotine or saline would be administered over 1 min. In the smoking study, volunteers were told they would be asked to smoke cigarettes with a low or high nicotine content under controlled conditions. After the study was completed, volunteers remained on the clinical research ward for 2 or more hours. Lunch was provided and vital signs were measured at 30-min intervals. When volunteers were medically stable and comfortable, they were discharged and transportation was provided. Volunteers were paid for their participation in the study, consistent with NIH regulations.

Smoking Abstinence Requirements

All men were asked to abstain from cigarettes and caffeinated beverages after midnight on the night before the study. Carbon monoxide (CO) levels were measured before the study to assess compliance with smoking abstinence requirements. Levels of breath carbon monoxide (CO) with a Vitalograph Breath CO Monitor (Vitalograph, Inc., Lenexa, KS) and breath alcohol levels were measured. Cigarette smokers with a CO level above 10 ppm were not allowed to participate in the study and, as shown in Table 1, average CO levels were below 5 ppm.

It is important for subject safety, as well as to avoid confounding of the dependent variables, to ensure that volunteers have not used any drugs before IV nicotine administration or cigarette smoking. On the morning of each study day, urine was collected and analyzed with a Triage® screen (smoking study) or an AmediCheck Instant Test Cup (IV nicotine study) to determine if illicit drugs were present. The Triage® Panel for Drugs of Abuse (Biosite Diagnostics, San Diego, CA) is a rapid multiple immunoassay system for the qualitative detection of the major metabolites of these drugs of abuse in urine at the following cut-off concentrations as recommended by the Substance Abuse and Mental Health Services Administration: Phencyclidine 25 ng/mL, Benzodiazepines 300 ng/mL, Benzoylecgonine, a metabolite of Cocaine, 300 ng/mL, Amphetamines 1,000 ng/mL, Tetrahydrocannabinol 50 ng/mL, Opiates 300 ng/mL and Barbiturates 300 ng/mL. The AmediCheck Instant Test Cup (Amedica Biotech, Inc., Hayward, CA) is an in vitro diagnosis for the following drugs in urine: THC 50 ng/mL, cocaine 300 ng/mL, amphetamine 1,000 ng/mL, methamphetamine 1,000 ng/mL, opiates 2,000 ng/mL, opiates 300 ng/mL, phencyclidine 25 ng/mL, barbiturates 300 ng/mL, benzodiazepines 300 ng/mL, methadone 300 ng/mL, oxycodone 100 ng/mL, MDMA 500 ng/mL, and tricyclic antidepressants 1,000 ng/mL.

Nicotine Dose Selection

Intravenous nicotine.

Nicotine doses were selected on the basis of previous clinical laboratory studies of the subjective effects of IV nicotine (Garrett & Griffiths, 2001; Jones et al., 1999; Jones & Griffiths, 2003; Soria et al., 1996). Nicotine [nicotine hydrogen (+) tartrate, the levo isomer of nicotine] was acquired from the New England Compounding Center (Framingham, MA) and dissolved in sterile saline (0.9% sodium chloride) for IV injection. The two doses of IV nicotine were prepared in concentrations of 1.0 mg/mL or 1.5 mg/mL. The unit doses are expressed as the nicotine base.

Cigarettes.

The effects of a high-nicotine cigarette and a low-nicotine cigarette were compared. The high-nicotine cigarette (Marlboro Red, Phillip Morris brand) contained 15.48 mg of nicotine and 16 mg of tar based on analysis by the Massachusetts Department of Public Health. In our previous studies, smoking a Marlboro Red cigarette under the conditions described below produced peak plasma nicotine levels above 20 ng/ml. The low-nicotine cigarettes contained 1.1 mg of nicotine and 2.8 mg of tar based on analyses provided by the manufacturer. We refer to this cigarette as low nicotine rather than as denicotinized, because most “denicotinized” cigarettes contain trace amounts of nicotine (<0.06–0.16 mg) (Pickworth, Fant, Nelson, Rohrer, & Henningfield, 1999; Robinson, Houtsmuller, Moolchan, & Pickworth, 2000; Shahan, Bickel, Madden, & Badger, 1999). Low-nicotine cigarettes were acquired from Murty Pharmaceuticals Inc. (Lexington, KY 40509).

Nicotine Administration Procedures

IV nicotine administration.

IV nicotine was administered in a bolus dose over 1 min. The volume to be infused (1.0 mg/70 kg or 1.5 mg/70 kg) was calculated based upon each man’s body weight.

Cigarettes.

Cigarettes were administered using a controlled smoking procedure designed to standardize puff volume and duration of inhalation (Griffiths, Henningfield, & Bigelow, 1982). Every 30 sec, men were asked to take one puff from a cigarette, hold the smoke for 5 sec, and exhale at the end of 5 sec. Men took 24 puffs over a 12-min smoking period with an interpuff interval of 25 sec. This is equivalent to approximately two cigarettes. A new lighted cigarette was presented after every four puffs so that changes in cigarette length would not influence puff duration (Nemeth-Coslett & Griffiths, 1984a, 1984b).

Cardiovascular Measures and Safety Precautions

Heart rate, blood pressure and electrocardiograms (ECG) were continuously monitored with a Hewlett-Packard EKG monitor (Model 78 352A) for 10 min prior to cigarette smoking and for 2 hours following cigarette administration. During IV nicotine administration, physiological monitoring was done with an InVivo Omni-Trak 3100 patient monitoring system, interfaced for computer acquisition of electrocardiogram (ECG), heart rate, enexpiratory carbon dioxide (EECO) and pulse oximetry. A physician certified in cardiopulmonary resuscitation was present during each study, and a cardiac defibrillator and appropriate emergency treatment medications were immediately available.

Visual Analog Scale (VAS)

Men were asked to rate how “high” they felt on a computerized presentation of a Visual Analog Scale of 0 to 100. Ratings were done at baseline, 10 min before nicotine administration. Then VAS ratings were repeated every 2 min for 20 to 30 min after IV nicotine administration or cigarette smoking began. Subjects were trained on the VAS after selection for the study, and again on each study day to maximize the accuracy of mood reports. The VAS has been shown to be reliable and sensitive to acute drug effects (Foltin & Fischman, 1991; Jasinski & Henningfield, 1989; Risinger et al., 2005; Walsh, Haberny, & Bigelow, 2000).

Blood Sample Collection

Baseline samples for nicotine analysis were collected 10 min before IV nicotine administration and cigarette smoking. After IV nicotine administration, blood samples were collected every 2 min for the first 16 min, then at 4 and 10 min for 30 min. After cigarette smoking began, blood samples were collected every 2 min for the first 20 min, and at 25, 30, 40, 50, 60, 80, and 120 min. Samples were collected in Vacutainer tubes without preservative. All samples were iced immediately, centrifuged and plasma was removed and frozen at −70 °C for nicotine and hormone analyses.

Plasma Nicotine Analysis

Plasma nicotine levels were measured in duplicate using a gas chromatography-mass spectrometry method described by Jacob and coworkers (Jacob, Wu, Yu, & Benowitz, 2000; Jacob, Wilson, & Benowitz, 1981; Jacob, Yu, Wilson, & Benowitz, 1991). The nicotine assay sensitivity was 1.0 ng/ml and the detection limit was 0.5 ng/ml. Interday and intraday variability of the assay were determined from the repeated analysis of spiked plasma samples. The mean coefficient of variation ranged from 1.1 to 7.8% for nicotine concentrations ranging from 1 to 100 ng/ml. No interference was found from various nicotine metabolites. Assay specificity was verified by comparing concentrations of nicotine in pooled smokers’ plasma determined by GCMS. Concentrations of nicotine were determined by gas chromatography with nitrogen-phosphorus detection (Jacob et al., 1981). Nicotine assays for both the IV nicotine and the smoking study were conducted in the laboratory of Peyton Jacob III, Ph.D., Division of Clinical Pharmacology of the Department of Medicine, University of California, San Francisco.

Statistical Analyses

Comparisons between the subjective and physiological effects of 1.5 mg/70kg and 1.0 mg/70kg IV nicotine, as well as high- and low-nicotine cigarettes were analyzed by a two-factor (route of administration × time) analysis of variance (ANOVA) for repeated measures. Within each route of administration a two factor (dose × time) ANOVA for repeated measures was conducted to determine significant differences between doses. If a significant main effect was found, Bonferroni post hoc tests were performed to identify the time points that differed significantly between the doses.

One complicating factor in this analysis was that an unequal number of subjects were studied after IV nicotine (N = 6–9 subjects) and smoked nicotine (N = 10) (see Table 1). Because effect size is resistant to the influence of sample size, this is a more sensitive measure of the magnitude of effect between variables (Ferguson, 2009). Accordingly, effect size was analyzed where appropriate. Eta squared was calculated for all comparisons to determine the magnitude of the differences observed, and Cohen’s proposed guidelines (Cohen, 1988) were used to interpret this value. Effects sizes were used to compliment interpretation of p values in order to estimate strength of the effect between variables (Ferguson, 2009). An ANOVA was also utilized to evaluate a change from baseline for each dose. If significant main effects were found, Dunnett’s Multiple Comparison Tests were performed to determine which time points were significantly different from the baseline. Demographic data (age, BMI, cigarettes per day and years of smoking), as well as baseline CO levels and plasma nicotine levels were analyzed with an ANOVA to determine possible differences between groups.

Results

Plasma Nicotine Levels after Low and High Doses of IV Nicotine

There were no significant differences in baseline plasma nicotine levels between the two IV nicotine dose groups (Figure 1, Table 1). After IV nicotine administration, nicotine plasma levels at doses of 1.0 mg and 1.5 mg/70 kg were significantly different (p < .001). The magnitude of the difference between means was large (± [1,137] = 61.38; p < .001). Partial eta squared = 0.48 (Cohen, 1988). The rate of increase in plasma nicotine levels was more rapid after the high dose of IV nicotine. Peak nicotine plasma levels averaged 6.25 ± 1.17 ng/ml at 6 min after low-dose IV nicotine and 12.36 ± 2.73 ng/ml at 4 min after the higher dose IV nicotine.

Figure 1. Plasma Nicotine Levels:

Figure 1.

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Plasma nicotine levels (ng/ml) after 1.0 or 1.5 IV nicotine (left panel) or after smoking a low- or high-nicotine cigarette (right panel). Plasma nicotine levels after low- (open circles) and high-dose IV nicotine (closed circles) are shown on the left ordinates. Plasma nicotine levels after smoking a low- (open symbols) and high-nicotine cigarette (closed symbols) also are shown on the left ordinate. Time (min) is shown on the abscissae. Points above BL were collected 10 min before IV nicotine administration or cigarette smoking began at time 0. The 12-min cigarette-smoking period is indicated by a gray rectangle. Each data point is the average (± SEM) of 6 or 9 men for each IV nicotine dose and 10 men for each smoking condition (N = 20). Statistical analysis indicated significant changes in plasma nicotine levels from baseline after IV nicotine administration in both the low dose (DF = 10.65, F = 5.113, p < 0.001) and high dose groups (DF = 10.92, F = 7.905, p < 0.001). After cigarette smoking, there were significant changes from the presmoking baseline in both the low nicotine (DF = 10.73, F = 3.380, p < 0.0014) and the high nicotine (DF = 10.109, F = 10.19, p < 0 .0001). Smoking data were adapted from Mendelson et al., 2005.

Plasma Nicotine Levels after Low- and High-Nicotine Cigarettes

There were no significant differences between the low- and high-nicotine cigarette groups in baseline nicotine levels before smoking began. Plasma nicotine levels increased significantly within 2 min, or four puffs on a high-nicotine cigarette, and remained significantly above baseline throughout the 120 min sampling period (p = .009–0.0001). Peak plasma nicotine levels of 23.90 ± 2.68 ng/ml were detected within 14 min after smoking onset, then plasma nicotine levels gradually decreased to 9.01 ± 1.25 ng/ml at the end of the sampling period. Plasma nicotine levels also increased significantly above baseline levels after smoking a low-nicotine cigarette (p = .03–0.0003). Peak plasma nicotine levels of 3.63 ± 0.59 ng/ml were detected within 12 min after low-nicotine cigarette smoking began. At the end of the sampling period plasma nicotine levels averaged 2.02 ± 0.31 ng/ml. Plasma nicotine levels were significantly higher after high-nicotine cigarette smoking than after low-nicotine cigarette smoking throughout the 120 min sampling period (p = .05–0.0001) (Figure 1, Table 1).

Comparisons of Plasma Nicotine Levels after IV Nicotine Administration and Cigarette Smoking

Baseline levels of nicotine were equivalent before IV nicotine administration or cigarette smoking. The nicotine plasma levels after low-dose IV nicotine administration were significantly higher than nicotine plasma levels measured after smoking a low-nicotine cigarette (p < .01). Post hoc tests showed that the points at 6 min were significantly different (p < .01). In contrast, plasma nicotine levels after smoking a high-nicotine cigarette were significantly higher than after administration of the higher IV dose of nicotine (p < .001). Post hoc tests showed that the points at 12, 14, 16, 20, and 30 min were all significantly different (p < .001). The magnitude of the differences in the means was large across all time points (eta squared = 0.49 to 0.62).

Ratings of Subjective “High” After IV Nicotine Administration and Cigarette Smoking

Figure 2 summarizes ratings of subjective “high” on a Visual Analogue Scale (VAS) after each dose of IV or smoked nicotine. There was no statistically significant difference between ratings of “high” after the low and high dose of IV nicotine at any point. However, ratings of “high” after smoking a high-nicotine cigarette were significantly greater than after smoking a low-nicotine cigarette at 0 to 12 min (p < .05–0.0001).

Figure 2. VAS Ratings of “high”:

Figure 2.

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Reports of subjective effects after a low- (open circles) or high- (closed circles) IV nicotine dose (left panel) or after smoking a low- (open symbols) or high- (closed symbols) nicotine cigarette. Subjective ratings on a Visual Analogue Scale (0–100) are shown on the left ordinate and time (min) is shown on the abscissae. Points above BL were collected 10 min before IV nicotine administration, or cigarette smoking began at time 0. The 12-min cigarette-smoking period is indicated by a gray rectangle. Each data point is the average (±) SEM of 6 or 9 men for IV nicotine and 10 men for each smoking condition (N = 20). Statistical analysis indicated significant changes in VAS “high” ratings from baseline after IV nicotine administration in both the low dose (p < 0.05) (DF = 1.65 F = 4.703) and high dose groups. (p < 0.05 (DF = 10.98 F = 6.454). After cigarette smoking, there were significant changes from the presmoking baseline in both the low- (DF = 18. F = 5.2, p = 0.01) and high- (DF = 18, F = 16.9, p < 0.0001) nicotine cigarette groups. “High” ratings after low- and high-nicotine cigarette smoking were adapted from Mendelson et al., 2005.

Comparison of Ratings of Subjective “High” After IV Nicotine Administration and Cigarette Smoking

“High” ratings after low dose IV nicotine were significantly greater than after smoking a low-nicotine cigarette at 2 min after drug delivery (p < .001, df = 1.154, F = 1.067). There were no significant differences in “high” ratings at any time point after the higher dose of IV nicotine and high-nicotine cigarette smoking.

Discussion

A major finding of this study was that peak plasma nicotine levels were significantly higher after 24 puffs on high-nicotine cigarettes than after administration of 1.5 mg/70 kg, IV nicotine, but peak VAS ratings of “high” were equivalent. Significant increases in plasma nicotine levels occurred slightly faster after cigarette smoking than after IV nicotine. Within 2 min (or four puffs) on a high-nicotine cigarette, plasma nicotine levels increased to 6 ng/ml. Whereas it took 4 min for plasma nicotine levels to reach a peak above 12 ng/ml after IV nicotine was administered over 1 min. Although the peak levels and the rate of increase of plasma nicotine during high-nicotine cigarette smoking was greater than after IV nicotine administration, the time course and overall level of VAS ratings of “high” were equivalent. Surprisingly, VAS ratings of “high” also did not differ after a low and high dose of IV nicotine, even though peak levels of nicotine differed significantly. In contrast, there was a significant difference in VAS ratings of “high” during smoking a low- and a high-nicotine cigarette.

There was also a temporal dissociation between VAS ratings of “high” and plasma nicotine levels after both IV nicotine administration and smoking a high-nicotine cigarette. VAS ratings began to decline abruptly while plasma nicotine levels were increasing. VAS ratings of “high” began to decrease within 4 min after IV nicotine injection, as plasma nicotine increased to peak levels. Similarly, during smoking a high-nicotine cigarette, the maximum ratings of “high” occurred within the first 4 min (or eight puffs) when plasma nicotine levels increased significantly from baseline. However after 6 min (or 12 puffs), when plasma nicotine levels exceeded 14 ng/ml, VAS ratings of “high” began to decrease. VAS ratings of “high” continued to decrease as plasma nicotine levels increased to peak at 23.9 ng/ml within 14 min after cigarette smoking began. Ratings of “high” were equivalent at 2 min after nicotine and smoked nicotine in the current study. At 2 minutes, men had inhaled only four puffs of nicotine whereas men in the IV group had received a bolus dose of 1.5 mg/70 kg IV nicotine. This suggests that a small amount of smoked nicotine can produce subjective effects similar to a bolus dose of IV nicotine.

Comparisons Between IV and Smoked Nicotine

An early study compared the subjective and physiological effects of IV nicotine (0.75, 1.5 and 3.0 mg) with three doses of cigarettes estimated to yield 0.4, 1.4, 2.9 mg of nicotine (Henningfield et al., 1985). That study did not use Visual Analog Scale ratings, so it is not possible to directly compare the findings with other clinical laboratory studies (Henningfield et al., 1985). However, the conclusion that IV and smoked nicotine had a similar profile of effects has been confirmed in most subsequent studies. It was also concluded that although IV and smoked nicotine had qualitatively similar effects, IV nicotine often produced larger effects (Henningfield et al., 1985). This conclusion is also consistent with our finding that the lower dose of IV nicotine produced significantly higher ratings of subjective “high” than smoking a low-nicotine cigarette.

As noted earlier, most clinical laboratory studies of IV nicotine have focused on pharmacodynamics and have not measured plasma nicotine levels. However many studies have used Visual Analog Scales (VAS), and have reported ratings of subjective “high.” In the present study, peak ratings of “high” were between 58 and 60 at 2 min after administration of a low and high dose of IV nicotine or smoking a high-nicotine cigarette. This “high” rating after smoking was only slightly greater than that measured at 2 min after administration of 3.0 mg/70 kg, IV nicotine (Jones et al., 1999). However, the “high” rating after 1.5 mg/70 kg, IV nicotine was less than 30 (Jones et al., 1999), or approximately one half of the peak “high” rating in the present study. In a comparison of responses to oral caffeine and IV nicotine in cocaine abusers, the peak high rating at 2 min was about 70 after 3.0 mg/70 kg IV nicotine, and less than 30 after 1.5 mg/70 kg IV nicotine (Garrett & Griffiths, 2001). In a study of the effects of oral caffeine maintenance on responses to IV nicotine (1.0 and 2.0 mg/70 kg) in cigarette smokers, caffeine significantly increased ratings of “high” (Jones & Griffiths, 2003). However, the highest VAS rating was less than 40 after administration of 2.0 mg/70 kg, IV nicotine (Jones & Griffiths, 2003). Although it is difficult to compare subjective VAS ratings across studies, we conclude that the “high” ratings reported by our subjects were equivalent to or greater than those previously reported.

Comparisons Between Venous Versus Arterial Samples for Nicotine Analysis

One limitation of the present study was that nicotine levels were analyzed from venous blood. Several studies have shown that nicotine concentrations measured in arterial blood are higher than in venous blood, and may provide a more accurate estimate of nicotine concentrations in brain (Gourlay & Benowitz, 1997; Henningfield & Keenan, 1993; Henningfield, London, & Benowitz, 1990; Henningfield, Stapleton, Benowitz, Grayson, & London, 1993; Rose, Behm, Westman, & Coleman, 1999). In one seminal study, arterial blood was sampled every 5 seconds during a controlled smoking procedure, and compared with matched IV nicotine doses delivered at the onset of each puff from a denicotinized cigarette (Rose et al., 1999). Under these conditions, arterial nicotine concentrations were two to three times higher than nicotine concentrations measured in venous blood (Rose et al., 1999). The peak arterial nicotine plasma concentration occurred slightly faster after smoking then after IV nicotine administration, but peaks were higher after IV nicotine (Rose et al., 1999). The temporal profile of nicotine plasma levels was similar after IV and smoked nicotine administration, and may reflect the fact that nicotine goes through the pulmonary circulation before systemic arterial circulation (Rose et al., 1999).

Positron emission tomography (PET) studies of radiolabeled nicotine can provide precise estimates of the time course of nicotine entry into brain tissue after smoked and IV nicotine (Berridge et al., 2010; Muzic, Berridge, Friedland, Zhu, & Nelson, 1998). After a single puff on a cigarette, nicotine entered the brain within 5 seconds, reached a maximum concentration within 1 min, and remained detectable in tissue for more than 15 min (Berridge et al., 2010). In comparison, IV nicotine (2.0 mg) took 75 seconds after injection to reach 20% to 80% of its maximum value in brain, whereas a single puff on a cigarette required only 30 seconds to reach the same level (Berridge et al., 2010; Muzic et al., 1998). Nicotine is thought to exert its reinforcing effects primarily via nicotinic acetylcholine receptors (nAChRs) on dopaminergic neurons (Benowitz, 2010; Picciotto et al., 1998; Watkins, Koob, & Markou, 2000), and these receptors are distributed widely throughout the brain (Buccafusco, 2004; Dani & Bertrand, 2007; Gotti et al., 2007; McGranahan, Patzlaff, Grady, Heinemann, & Booker, 2011). In addition to traditional reward pathways, a high density of nicotine receptors has been detected in anterior cingulate, the caudate nucleus, thalamus, cortex, and cerebellum (Brody, 2006; Koob & Volkow, 2010). The rate at which nicotine activates/deactivates these areas remains to be determined.

Conclusions

Clearly, the relationship between subjective effects ratings and plasma drug levels is complicated and may vary as a function of the drug, as well as the route of administration and venous or arterial measures of drug blood levels. In the present study, subjective “high” ratings were equivalent after IV and smoked nicotine, even though peak plasma nicotine levels measured in venous blood were significantly higher after smoking. The rate of increase in nicotine plasma levels after IV nicotine and smoking was similar. In a study of subjective responses to oral pentobarbital, peak plasma levels were equivalent after single dose and multiple dose administration (de Wit et al., 1992). However ratings of “high” on a Visual Analogue Scale were significantly greater after a single dose when plasma levels increased rapidly, than when a higher dose of pentobarbital was administered in six divided doses (de Wit et al., 1992). After smoked and IV cocaine, arterial plasma cocaine concentrations were higher than venous cocaine concentrations, but the rate of increase was the same (Evans, Cone, & Henningfield, 1996). Maximal cocaine concentrations were detected within 15 sec after both smoked and IV cocaine, and Visual Analog Scale measures of “high” and “stimulated” did not differ significantly as a function of the route of administration (Evans et al., 1996). As neuroimaging techniques provide more accurate measures of when drugs enter the brain, the sequence of areas affected, and the temporal relation to concurrent measures of subjective effects and arterial and/or venous measures of drug blood concentrations, the relation between biological and subjective measures may be clarified.

Acknowledgments

All authors contributed in a significant way to the manuscript and all authors have read and approved the final manuscript. All authors report that there are no conflicts of interest. This research was supported in part by NIDA Grants R01-DA 025065, R01-DA 15067, and K05-DA 00101. The funding source had no role other than financial support. We thank our clinical research staff who contributed to these studies. We are especially grateful to Drs. Arthur J. Siegel, N.V. Goletiani, and M.B. Sholar for their contributions to these studies.

Contributor Information

Nancy K. Mello, Alcohol and Drug Abuse Research Center, Harvard Medical School

Mackenzie R. Peltier, Alcohol and Drug Abuse Research Center, Harvard Medical School

Haley Duncanson, Department of Psychology, Suffolk University.

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