The Effects of Changes in Cigarette Menthol Content on Acute Nicotine Pharmacology and Smoking Topography.

INTRODUCTION: Menthol influences the appeal and addictiveness of cigarette smoking, however the data regarding menthol's effects on nicotine pharmacokinetics (PK) and smoking topography are inconsistent. This study investigated the impact of different cigarette menthol levels on nicotine pharmacology and smoking topography in current menthol smokers. AIMS AND METHODS: The study was a double-blind, randomized, four-period, crossover study to investigate the effects of smoking cigarettes with varying menthol content (0, 3, 6, and 12 mg menthol) on nicotine PK, smoking topography, and subjective effects in current menthol smokers. Each experimental session consisted of a prescribed use session, followed by 145 min of no smoking and a 1-h ad libitum smoking session. Serial blood samples were collected; smoking topography was recorded using CReSS Lab topography device. RESULTS: There was no significant effect of menthol on nicotine PK after prescribed smoking of cigarettes with varying menthol contents. During ad libitum smoking, there was significantly smaller total puff volume and puff duration in the 12 mg menthol condition compared to other menthol conditions. Subjective and sensory measures indicated significantly higher overall positive ratings for the 3 mg and 6 mg menthol cigarettes compared to the 0 mg menthol cigarette; the 12 mg menthol cigarette was less liked and harsher than the 3 mg condition. CONCLUSIONS: These findings suggest that menthol, at concentrations reflecting the marketplace (3-6 mg), contributes to positive subjective smoking experiences among menthol smokers, but does not have a significant effect on nicotine PK or smoking topography in an acute laboratory setting. IMPLICATIONS: While our data indicate that varying menthol content does not have a significant impact on nicotine's pharmacological effects under acute exposure conditions, these data highlight the contribution of menthol's flavor and sensory effects to product preference and positive smoking experiences, which facilitate repeated experimentation, progression to regular use, and subsequent dependence.

A Method to Amend Cigarettes With Menthol for Use in Research.

INTRODUCTION: Studies have evaluated the role of menthol cigarettes on various addiction-related outcomes; however, the effect of varying menthol content on these outcomes has not been evaluated. We developed a method to amend non-menthol SPECTRUM Research Cigarettes to contain menthol at four different levels. AIMS AND METHODS: SPECTRUM Research Cigarettes, NRC 600 (0.8 mg nicotine; 10 mg tar), were modified to contain target menthol amounts at 3, 6, and 12 mg/cigarette by injecting 25 µL ethanol/triacetin/menthol solutions of varying concentrations (120 mg menthol/mL, 240 mg/mL, and 480 mg/mL) into four distinct locations in the filter and tobacco rod. Menthol content was tested in triplicate in the whole cigarette and in the tobacco rod and filter at 1, 24, 48, and 72 hours for each target menthol level using an extraction solution of quinoline in methyl-tert-butyl ether and measured using gas chromatography with flame ionization detection. RESULTS: Injections into the filter and tobacco rod (12.5 µL each) yielded equal menthol distribution up to 72 hours. However, total menthol content decreased from an average of 90.3% of the target menthol concentration at 1 hour to 80.7% at 72 hours in cigarettes stored individually in glass tubes at room temperature. Analysis of urinary menthol glucuronide confirmed that amended cigarettes used within 24 hours of injection delivered dose-related menthol levels to participants in a clinical laboratory setting. CONCLUSION: This method can be used to modify cigarettes with a range of reliable menthol levels in both filter and tobacco rod for use in laboratory and clinical research. IMPLICATIONS: This study presents a technique for modifying cigarettes with different levels of menthol that can reliably deliver dose-related menthol levels to participants when smoked in a clinical study. The technique can be used to quickly amend cigarettes to examine the independent effects of varying flavor and additive levels on smoking behavior, nicotine pharmacokinetics, mainstream smoke emissions, and other laboratory or clinical research outcomes.

Formulation of smokeless tobacco products with a wide range of pH to study nicotine pharmacokinetics and pharmacodynamics.

The rate of nicotine absorption from tobacco products is a determinant of addiction potential and other detrimental health effects. Oral nicotine bioavailability from moist snuff smokeless tobacco (ST) is influenced by nicotine content, pH, flavors, and tobacco cut. For use in a clinical study testing the effect of pH on nicotine pharmacokinetics, four investigational ST products that differed only in pH were produced. A commercial ST product (Copenhagen Long Cut Original, pH 7.7) was modified with citric acid monohydrate (23 mg/g tobacco) or sodium carbonate (4.6 and 11 mg/g) to create products with pH 5.0, 8.2, and 8.6, respectively. All products - including the original product with pH 7.7 - were individually packaged (approximately 2 g) in aluminum foil pouches and stored frozen (-20 °C); pH, nicotine, tobacco-specific nitrosamines, moisture content, and mold and yeast counts were tested for up to 19 months to verify stability. Remarkable stability was demonstrated in this packaging/storage combination. For example, pH from all products were within 0.1 pH units and never exceeded 0.2 units. Nicotine concentration averaged 9.07 mg/g at baseline, maximal deviations from baseline in the four products averaged 0.30 mg/g. Similarly, TSNA, moisture content, yeast, and mold did not materially change. This study illustrates a method of investigational tobacco products formulation by manipulating a single design feature (or component) with the purpose of independently and systematically assessing its influence on nicotine bioavailability in a clinical study.

The pH of Smokeless Tobacco Determines Nicotine Buccal Absorption: Results of a Randomized Crossover Trial.

Nicotine absorption rate influences tobacco products' addictiveness. For smokeless tobacco, nicotine buccal absorption is associated with its free-base form; the pH of smokeless tobacco defines the proportion of free-base (i.e., unprotonated) vs. protonated nicotine. This was the first study to compare nicotine pharmacokinetics (PK) and pharmacodynamics (PD) after the use of commercial smokeless tobacco products that were experimentally manipulated to differ only in pH and percent free-base nicotine. Moist snuff users (N = 40) completed four crossover visits and used a single 2 g portion of Copenhagen Original Long Cut amended to 4 pH levels: 5.0, 7.7, 8.2, and 8.6 (free-base nicotine 0.1, 32, 60, and 79%) for 30 minutes. Nicotine PK and PD were assessed for 4 hours post-use. Nicotine PK substantially depends on its free-base proportion, with more than 4-fold increases in mean plasma nicotine maximum concentration and area under the curve over 240 minutes (3.9 to 16.7 ng/mL; 385 to 1810 ng min/mL, respectively, both P < 0.001) from pH 5.0 to 8.6. The autonomic cardiovascular effects of smokeless tobacco use reflected percent free-base nicotine, with small (albeit significant) systematic increases in heart rate and blood pressure associated with free-base nicotine. Smokeless tobacco product pH and percent free-base nicotine play a major role in the rate and extent of nicotine absorption, determining product PD effects and abuse potential. Research and regulation of smokeless tobacco products should consider both total nicotine content and product pH. Further research may address the impact of modifying pH on the addictiveness of smokeless tobacco and associated use behaviors.

Nicotine and carbon monoxide exposure from inhalation of cigarillo smoke.

BACKGROUND: There has been an increase in the use of cigarillos in the US. People who smoke cigarillos typically also regularly smoke cigarettes (dual users). METHODS: We compared puffing topography, biomarkers of acute exposure [exhaled carbon monoxide (COex) and plasma nicotine] and physiologic effects from usual brand cigarette and Black & Mild cigarillo smoking in dual users (N=23) in two laboratory sessions. RESULTS: Participants (21 men) smoked an average of 17.5cigarettes/day. Cigarillo consumption varied widely from as few as 1/week to daily. Participants were highly nicotine dependent (average FTND score: 6.3). There were statistically significant differences in smoking behavior between cigarette and cigarillo smoking in time to smoke, number of puffs, and total puff volume (all P<0.001). Average puff duration, interpuff interval average puff volume, and puff velocity did not differ between cigarettes and cigarillos. Nicotine boost was similar after both cigarettes and cigarillos. COex boost was significantly greater after cigarillo smoking compared to cigarette smoking (P<0.001). CONCLUSIONS: The smoking pattern and exposure profile indicate that dual users inhale cigarillo smoke just as they inhale cigarette smoke thereby exposing themselves to considerable amounts of nicotine and other components of tobacco smoke. COex exposure results imply that cigarillo smoking may be associated with higher exposure to smoke-delivered volatile components of mainstream cigarillo smoke including carcinogens when compared to cigarettes. IMPACT: The findings that cigarillos and cigarettes are smoked similarly in dual users are relevant to health and regulatory considerations on cigar products.

Nicotine delivery and pharmacologic response from Verve, an oral nicotine delivery product.

Verve, an oral nicotine delivery product (ONDP), was introduced by Nu Mark (Altria Client Group, Richmond VA) for smokers to use in places where smoking is prohibited. This study assessed the effect of this ONDP on plasma nicotine levels, heart rate, product satisfaction, and ability to suppress smoking urge and cigarette cravings. Thirteen daily cigarette smokers [8 men and 5 women; average age 33.4years] attended two laboratory sessions, one occurred after overnight tobacco abstinence. Plasma samples were collected before and after ONDP use and measured for nicotine. In non-abstinent smokers, mean plasma nicotine levels increased from 18.3 to 21.0ng/mL. In abstinent smokers, average nicotine levels increased from 3.1 to 4.5ng/mL. After overnight tobacco abstinence, ONDP use significantly (p<0.01) increased heart rate from 69beats per minute (bpm) to 75bpm; while urge to smoke decreased significantly (p<0.01) from a score of 8.6 to 4.9. Participants indicated moderate product satisfaction that was not changed by tobacco abstinence. Analysis of unused ONDP revealed total nicotine levels of 1.68±0.09mg/disc. Spent ONDP discs were also analyzed to determine % nicotine liberated during chewing; results were 80% in the non-abstinent and 82% in the abstinent conditions (ns). Our study results indicate that ONDP use can increase plasma nicotine levels and heart rate and reduce cigarette cravings in abstinent smokers.

Make your own cigarettes: toxicant exposure, smoking topography, and subjective effects.

BACKGROUND: Despite considerable use of make your own (MYO) cigarettes worldwide and increasing use in the United States, relatively little is known about how these cigarettes are smoked and the resultant toxicant exposure. METHODS: In a laboratory study, we compared two types of MYO cigarettes-roll your own (RYO) and personal machine made (PMM)-with factory-made (FM) cigarettes in three groups of smokers who exclusively used RYO (n = 34), PMM (n = 23), or FM (n = 20). Within each group, cigarettes were smoked in three conditions: (i) after confirmed overnight tobacco abstinence; (ii) in an intense smoking paradigm; and (iii) without restrictions. All cigarettes were smoked ad lib through a smoking topography unit. RESULTS: Plasma nicotine significantly increased after cigarettes in all conditions except PMM in the intense smoking paradigm. Puff volume, puff duration, total puff volume, and puff velocity did not differ between cigarette types but the puffs per cigarette and time to smoke were significantly smaller for RYO compared with PMM and FM. Regardless of the cigarette, participants consumed the first three puffs more vigorously than the last three puffs. CONCLUSIONS: Despite the belief of many of their consumers, smoking MYO cigarettes is not a safe alternative to FM cigarettes. Like FM, MYO cigarettes expose their users to harmful constituents of tobacco smoke. Despite differences in size and design their puffing profiles are remarkably similar. IMPACT: These data are relevant to health and regulatory considerations on the MYO cigarettes.