Results

Figure 1 illustrates the time course of nicotine plasma concentrations, heart rate, and subjective ratings of drug strength for each of the five products tested. Table 1 compares the peak effects and AUC values between products on plasma nicotine concentrations, heart rate, blood pressure, and subjective ratings of drug strength.

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Figure 1

Mean plasma nicotine concentration, heart rate, and visual analogue scale (VAS) score (product “strength”) after administration of each of four smokeless tobacco products, or mint snuff.

Pretreatment plasma nicotine concentrations averaged 5.3 ng/ml (SD 5.4) and mean baseline concentrations were similar across treatment conditions. The maximum mean increase in plasma nicotine concentration was highest for Copenhagen (mean = 19.5 ng/ml). Lower increments in nicotine concentrations were shown for Skoal Long Cut Cherry and Skoal Original Wintergreen which increased nicotine concentrations an average of 14.9 ng/ml. Only small increases in nicotine concentration were shown for Skoal Bandits, which increased nicotine concentrations an average of 4.2 ng/ml. Two of the subjects showed no increase in plasma nicotine concentrations after administration of Skoal Bandits. Similarly, AUC values for plasma nicotine concentrations during the 30 minutes in which the snuff was held in the mouth were highest for Copenhagen, lower for Skoal Long Cut Cherry and Skoal Original Wintergreen, and much lower for Skoal Bandits.

The average time taken to reach peak nicotine concentrations (T_max) was similar across the snuff products with peak concentrations generally being reached 5–10 minutes before or after removal of snuff from the mouth. Plasma nicotine concentrations increased much more rapidly following administration of Copenhagen than for Skoal Original Wintergreen and Skoal Long Cut Cherry. After administration of Copenhagen, average nicotine concentrations of 10 ng/ml were reached within four minutes of administration, and levels of 15 ng/ml were reached within six minutes. In contrast, after administration of Skoal Original Wintergreen, levels of 10 ng/ml and 15 ng/ml were reached after 10 and 20 minutes; these same levels were reached 15 and 25 minutes after administration of Skoal Long Cut Cherry.

Pretreatment heart rate values averaged 72.2 beats per minute and pretreatment blood pressure values averaged 124.4/72.9 mm Hg. Average pretreatment values on these cardiovascular measures were similar for all treatment conditions. The peak increase in heart rate relative to baseline was significantly greater for Copenhagen, Skoal Long Cut Cherry, and Skoal Original Wintergreen than for Skoal Bandits or mint snuff. There were no significant differences between Copenhagen, Skoal Long Cut Cherry, and Skoal Original Wintergreen in average peak increase in heart rate, and there was no difference between mint snuff and Skoal Bandits. AUC values were significantly different between mint snuff and Copenhagen only. As figure 1 shows, average heart rate peaked about 15 minutes after the product was placed in the mouth. The peak increase in systolic blood pressure was not significantly different between conditions. The AUC values for systolic blood pressure were significantly higher during Copenhagen administration than for any other condition; values for all of the tobacco snuff products were significantly higher that for mint snuff. The peak increase in diastolic blood pressure was not significantly different between conditions. The AUC values for diastolic blood pressure were significantly higher for Copenhagen, Skoal Long Cut Cherry, and Skoal Original Wintergreen than for mint snuff.

Peak subjective ratings of product strength were highest for Copenhagen, followed by Skoal Original Wintergreen, and Skoal Long Cut Cherry; each of these produced significantly higher peak ratings than mint snuff or Skoal Bandits. The AUC values of these ratings were significantly higher for Copenhagen than for any other product tested. In addition, the AUC values of these ratings were significantly higher for Skoal Original Wintergreen and Skoal Long Cut Cherry relative to mint snuff or Skoal Bandits. There was no significant difference between mint snuff and Skoal Bandits on this measure. As shown in figure 1, scores generally peaked around 10–15 minutes after the product was placed in the mouth.

Table 2 compares the mean responses on subjective ratings between products. Copenhagen produced the highest ratings on measurers of: overall product strength, increased salivation, nausea, heart racing, head rush, anxious, and feeling alert, and the lowest rating of how well packed. In general, scores on these measures were somewhat lower for Skoal Long Cut Cherry and Skoal Original Wintergreen, and lowest for mint snuff and Skoal Bandits. There were no significant differences between Skoal Bandits and mint snuff on any of these subjective measures.

Discussion

The study clearly shows that large amounts of nicotine are delivered rapidly to the bloodstream during use of moist snuff. In fact, venous nicotine concentrations are as high, or higher, than those that have been observed following cigarette smoking. For example, Benowitz et al found that average peak blood nicotine concentrations increased 14.3 ng/ml after smoking one cigarette or using 2.5 g moist snuff for 30 minutes.11Another study found similar increases of 14.5 ng/ml produced by 2 g of Swedish snuff.13 The current study found peak plasma nicotine concentrations increased as much as 19.5 ng/ml after administration of 2.0 g Copenhagen held in the mouth for 30 minutes, and slightly lower amounts, 14.9 ng/ml, produced by Skoal Long Cut Cherry and Skoal Original Wintergreen. Skoal Bandits produced only small increases in peak plasma nicotine concentration, 4.2 ng/ml, an increase not significantly greater than non-tobacco, non-nicotine mint snuff. This relatively small increase in peak plasma nicotine concentration produced by Skoal Bandits was at least partly due to the fact that each pouch contains 0.5 g of tobacco, compared with the 2 g of tobacco administered in the other product conditions. It should be noted that there was considerable variation among individuals in the amount of nicotine absorbed from smokeless tobacco, even though they all placed the same-sized dose in their mouths. This is consistent with the variability found in previous research by Benowitzet al. 11 Differences between individuals in nicotine absorption may have been due to a variety of factors including individual differences in saliva pH, rate of salivation and expectoration, and differences in mucosal characteristics.

Absorption of nicotine from moist snuff occurs primarily across the oral mucosa. As shown in the figure, the rate of absorption was highest when the snuff was first placed in the mouth, and plasma concentrations continued to rise until the stuff was removed from the mouth. Absorption continued even after the snuff was removed in some subjects, presumably because of the slow release of nicotine from the mucosa into the plasma or absorption of swallowed nicotine in the gut.

Henningfield et al reported that Copenhagen, Skoal Original Wintergreen, and Skoal Long Cut Cherry have comparable nicotine content (11.4, 10.4, and 11.4 mg/g, respectively), but produce different pH values in suspension (8.6, 7.6, and 7.5, respectively).8 Because of the different pH values of these products in suspension, one would expect nicotine bioavailability to be much greater for Copenhagen than for Skoal Wintergreen and Skoal Long Cut Cherry. Indeed, nicotine delivery was shown to be significantly higher and faster for Copenhagen than for these other two products. Thus the results of the present study confirm that the pH of these products in suspension is a significant factor in determining nicotine bioavailability and absorption and that products with similar nicotine content can deliver significantly different amounts of nicotine.

Nicotine administration from smoked tobacco increases heart rate and blood pressure.14 The current study demonstrated increased heart rate after moist snuff administration that was associated with the nicotine levels attained by each product. Heart rate increased significantly following administration of Copenhagen, Skoal Original Wintergreen, and Skoal Long Cut Cherry, relative to mint snuff or Skoal Bandits. Heart rate increases followed a similar time course as the plasma nicotine levels during the first 15 minutes of administration; however, heart rate levelled off or declined after about 15 minutes of administration despite continued increases in nicotine plasma concentration, possibly because of acute tolerance development. This levelling of heart rate after 15 minutes of administration despite continued increases in nicotine plasma concentration was also shown by Benowitz et al.11

Subjective effects of moist snuff were also associated with the changes in plasma nicotine concentrations. Peak changes in scores on the measure of “product strength”, taken at each timepoint that plasma was drawn, were highest for Copenhagen, lower for Skoal Original Wintergreen and Skoal Long Cut Cherry, and lowest for mint snuff and Skoal Bandits. As with heart rate, increases in subjective ratings showed a similar timecourse as plasma concentration during the first 10–15 minutes of administration; however, subjective ratings levelled or dropped 10–15 minutes after administration, an effect that may be related to acute tolerance development. It should be noted that, whereas the majority of the subjects typically used Copenhagen, there was variability between subjects in their brand of choice. It is possible that the individual subjects' brand of choice may have influenced their self-report of subjective effects. For example, subjects who typically used Copenhagen may have reported low ratings of other products because they could tolerate higher nicotine concentrations. In contrast, subjects who typically used a product that delivers less nicotine might have over-rated the strength of Copenhagen because of lack of tolerance.

The results of the present study have important public health implications. First, the rapid delivery of high doses of nicotine from moist snuff products such as Copenhagen, Skoal Original Wintergreen, and Skoal Long Cut Cherry are sufficient to produce and maintain nicotine dependence. The production of dependence is important because it causes young experimenters to progress to regular use, and regular users to continue use despite negative health consequences. A study by Holm et al found no significant differences between cigarette smokers and snuff users on measures of: unpleasantness of abstaining for an hour or two, self-perceived addiction, craving for tobacco, or difficulty in giving up use.13 In our study, nine out of 10 subjects reported failed quit attempts.

Secondly, the fact that the lower pH products, such as Skoal Bandits, deliver only small amounts of nicotine at a slower rate to users is consistent with the designation and marketing as “starter” products by at least one smokeless tobacco company.15 In addition to the lower pH, Skoal Bandits contain less tobacco (0.5 g) than is typically used by consumers of snuff that is not marketed in pouches. Because of the lower nicotine absorption, these products may be used by young consumers, who have little experience with nicotine, without producing nausea and vomiting associated with high dose administration to people who have little nicotine tolerance.

Thirdly, the marked cardiovascular effects produced in this study by high nicotine yield snuff products suggests that the cardiovascular hazards of smoking that may be related to nicotine, such as coronary artery disease and hypertension, would also be expected with smokeless tobacco use. These adverse effects of nicotine are in addition to other risks of snuff, such as oral cancers, which are related to the high nitrosamine content of commercial snuff in the United States.16 17

In summary, this study shows that snuff products are capable of rapidly delivering high doses of nicotine. Rapid, high-dose delivery of nicotine can lead to nicotine dependence. Long-term use of snuff can lead to a number of adverse health effects including oral cancers, cardiovascular diseases, and gingival diseases. For these reasons, it is important that the public health community consider oral snuff use as a burden on public health in the same way that cigarette smoking is recognised.