Comparative Evaluation of Nicotine Analogs

PRIMARY OBJECTIVES: I. To assess the subjective effects and behavioral economic demand of 6-methyl nicotine (6-MN) and nicotinamide. II. To assess the use topography of 6-MN and nicotinamide. III. To conduct exploratory pharmacokinetics of 6-MN and nicotinamide. IV. To assess the acute effects of 6-MN and nicotinamide on cardiovascular health. OUTLINE: Participants are randomized to 1 of 6 intervention sequences. SEQUENCE 1: VISIT 1: Participants take 1 puff of nicotine EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotine EC as much or as little as they like over 1 hour. VISIT 2: Participants take 1 puff of 6-MN EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use 6-MN EC as much or as little as they like over 1 hour. VISIT 3: Participants take 1 puff of nicotinamide EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotinamide EC as much or as little as they like over 1 hour. SEQUENCE 2: VISIT 1: Participants take 1 puff of nicotine EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotine EC as much or as little as they like over 1 hour. VISIT 2: Participants take 1 puff of nicotinamide EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotinamide EC as much or as little as they like over 1 hour. VISIT 3: Participants take 1 puff of 6-MN EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use 6-MN EC as much or as little as they like over 1 hour. SEQUENCE 3: VISIT 1: Participants take 1 puff of nicotinamide EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotinamide EC as much or as little as they like over 1 hour. VISIT 2: Participants take 1 puff of 6-MN EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use 6-MN EC as much or as little as they like over 1 hour. VISIT 3: Participants take 1 puff of nicotine EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotine EC as much or as little as they like over 1 hour. SEQUENCE 4: VISIT 1: Participants take 1 puff of nicotinamide EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotinamide EC as much or as little as they like over 1 hour. VISIT 2: Participants take 1 puff of nicotine EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotine EC as much or as little as they like over 1 hour. VISIT 3: Participants take 1 puff of 6-MN EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use 6-MN EC as much or as little as they like over 1 hour. SEQUENCE 5: VISIT 1: Participants take 1 puff of 6-MN EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use 6-MN EC as much or as little as they like over 1 hour. VISIT 2: Participants take 1 puff of nicotine EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotine EC as much or as little as they like over 1 hour. VISIT 3: Participants take 1 puff of nicotinamide EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotinamide EC as much or as little as they like over 1 hour. SEQUENCE 6: VISIT 1: Participants take 1 puff of 6-MN EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use 6-MN EC as much or as little as they like over 1 hour. VISIT 2: Participants take 1 puff of nicotinamide EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotinamide EC as much or as little as they like over 1 hour. VISIT 3: Participants take 1 puff of nicotine EC every 30 seconds over 5 minutes for a total of 10 puffs in the absence of unacceptable toxicity. Sixty minutes later, participants use nicotine EC as much or as little as they like over 1 hour. Additionally, all patients undergo urine sample collection during screening and blood sample collection on study. Among enrolled current EC users, cardiovascular measurements and biochemical analyses of endothelial function will be conducted in a subset of the participants. After completion of study intervention, participants are followed up at 4 and 12 weeks.